Sunless tanning compounds and compositions

ABSTRACT

The invention provides sunless tanning compositions comprising a compounds of formula (I): or a salt thereof as described herein as well as methods for tanning mammalian skin by contacting the skin with the compounds of formula (I) or compositions comprising compounds of formula (I).

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.61/842,717 that was filed Jul. 3, 2013. The entire content of thisprovisional application is hereby incorporated herein by reference.

BACKGROUND OF THE INVENTION

The sun's rays are known to produce ultraviolet radiation, such assunburn that can have detrimental effects on the skin. Excessiveexposure can lead to skin wrinkling, age spots, and even skin cancer.Skin cancer is the most common cancer diagnosed in the United States andthe incidence of skin cancer continues to rise. Epidemiological studieshave documented that extensive sun exposure increases the risk ofdeveloping non-melanoma skin cancer. Photo-protection is the primarypreventative health strategy and sunscreens are one of the mostimportant forms of photoprotection.

As people become more aware of the harmful effects of the sun, productssuch as sunless tanning products or self-tanning products are gainingpopularity. These products typically employ a sunless tanning agent,such as dihydroxyacetone to impart color onto the skin that provides theimpression of a tan produced by exposure to the sun. Many individualshave a skin complexion which does not tan readily on exposure tosunlight. Others achieve a tan only with great discomfort and possiblyadverse effects to the skin due to exposure to sun's rays, e.g.,sunburn. Yet, attainment of a tan is highly desired by many individualsfor cosmetic and other reasons, especially if this can be accomplishedeffectively without the usual exposure to the sun, i.e., throughskin-tanning agents.

In other instances, individuals who tan with difficulty may desire toenhance or extend the life of a naturally acquired tan withoutre-exposure to the sun. Also, a suntan may be desired when weatherconditions do not permit the sun exposure necessary to acquire a tan.Acquisition of a natural tan by exposure to the sun may be almostimpossible for those very light skin persons who tend to burn ratherthan tan, In addition, the deleterious effects of excessive exposure tosunlight are becoming more generally recognized.

It is known that an artificial tan can be achieved by applyingskin-tanning agents to the human skin in a suitable vehicle or base.Examples of known skin-tanning agents include hydroxyaldehydes, such asdihydroxyacetone, (U.S. Pat. No. 2,949,403 and U.S. Pat. No. 5,232,688)and imidazole derivatives, such as 4-(hydroxymethylimidazole) (U.S. Pat.No. 5,252,322).

Dihydroxyacetone is reported to react with skin proteins and amino acidsto elicit its skin coloring effect and many compositions usingdihydroxyacetone as an active ingredient have been reported includingtopical composition further containing various dyes, such as catchpowder, dogwood powder and walnut powder which are intended to offsetthe undesirable orange cast or hue which results from the use ofdihydroxyacetone on fair skinned humans (U.S. Pat. No. 4,708,865). Otherdihydroxyacetone compositions contain sunscreen compounds, such as octyldimethyl PABA (U.S. Pat. No. 4,434,154 and U.S. Pat. No. 3,177,120).Further, dihydroxyacetone has been formulated into oil-in-wateremulsions, into preparations containing up to 50% alcohol which tend todry the skin, and into “creamy bases”, such as are found in hand andface lotions and creams. U.S. Pat. No. 5,232,688 discloses compositionsfor self-tanning of skin which include an alpha-hydroxy substitutedketone or aldehyde, such as dihydroxyacetone or erythrulose, apolyacrylamide, and a pharmaceutically-acceptable carrier.

There is a need for further sunless tanning agents and compositionscomprising such agents.

SUMMARY OF THE INVENTION

In an aspect of the invention there is provided a sunless tanningcomposition comprising a a compound of formula I:

wherein:

each R¹ is independently H, (C₁-C₆)alkyl, (C₃-C₇)carbocycle orR_(a)C(═O)—, and the two R⁴ groups together form a —(C₃-C₈)alkyl- group,a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl- group or a—(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; or

each R⁴ is independently H, (C₁-C₆)alkyl, (C₃-C₇)carbocycle orR_(a)C(═O)—, and the two R¹ groups together form a —(C₃-C₈)alkyl- group,a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl- group or a—(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; or

the two R⁴ groups together form a —(C₃-C₈)alkyl- group, a—(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl group or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl-group and the two R¹ groups together form a —(C₃-C₈)alkyl- group, a—(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl- group or a—(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl-group;

the dashed bonds labeled “a” are absent and the dashed bonds labeled “b”are double bonds; or all the dashed bonds are single bonds;

R² is H, (C₁-C₆)alkyl or aryl, wherein aryl is optionally substitutedwith one or more Z¹ groups;

R³ is H, (C₁-C₆)alkyl or aryl, wherein aryl is optionally substitutedwith one or more Z¹ groups;

Y is O, S, NH, NR_(c), P, P(═O) or POH;

Y′ is Si(R_(b))₂ or —Si(R_(b))₂—O—Si(R_(b))₂—;

each R_(a) is independently (C₁-C₆)alkyl, (C₃-C₇)carbocycle or aryl,wherein aryl is optionally substituted with one or more Z¹ groups;

each R_(b) is independently (C₁-C₆)alkyl, (C₃-C₇)carbocycle or aryl,wherein aryl is optionally substituted with one or more Z¹ groups;

each R_(c) is independently R_(g) or a C₁-C₁₈ saturated or unsaturatedcarbon chain that is optionally substituted with one or more groupsindependently selected from oxo (═O), hydroxy, mercapto, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, NR_(d)R_(e), carboxy, andaryl, wherein any aryl of R_(c) is optionally substituted with one ormore R_(f);

each R_(d) and R_(e) is independently selected from H, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, phenyl, benzyl, and R_(g);

each R_(f) is independently selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, —C(═O)-phenyl, and—C(═O)CH₂C(═O)-phenyl, wherein any phenyl is optionally substituted withone or more groups independently selected from (C₁-C₆)alkyl, —SO₃H, and(C₁-C₆)alkoxy;

-   -   each R_(g) is

each Z¹ is independently selected from (C₁-C₆)alkyl, halogen, —CN,—OR_(n1), —NR_(q1)R_(r1), —NR_(n1)COR_(p1), —NR_(n1)CO₂R_(p1), NO₂,—C(O)R_(n1), —C(O)OR_(n1) and —C(O)NR_(q1)R_(r1), wherein any(C₁-C₆)alkyl of Z¹ is optionally substituted with one or more (e.g. 1,2, 3, 4, 5 or 6) halogen;

each R_(n1) is independently selected from H and (C₁-C₆)alkyl, whereinany (C₁-C₆)alkyl of R_(n1) is optionally substituted with one or more(e.g. 1, 2, 3, 4, 5 or 6) halogen;

each R_(p1) is independently (C₁-C₆)alkyl; and

R_(q1) and R_(r1) are each independently selected from H and(C₁-C₆)alkyl or R_(q1) and R_(r1) together with the nitrogen to whichthey are attached form a piperidine, pyrrolidine, morpholine, azetidine,thiomorpholine, piperazine or 4-methylpiperazine;

or a salt thereof.

In another aspect, there is provided a sunless tanning compositioncomprising a compound of formula II:

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier,

wherein:

R¹ is H, (C₁-C₆)alkyl, (C₃-C₇)carbocycle or R_(a)C(═O)—;

R² is H, (C₁-C₆)alkyl or aryl, wherein aryl is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

R⁴ is H, (C₁-C₁₀)alkyl, (C₃-C₇)carbocycle or R_(a)C(═O)—;

R_(a) is or (C₁-C₆)alkyl, (C₃-C₇)carbocycle or aryl, wherein aryl isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹groups;

each Z¹ is independently selected from (C₁-C₆)alkyl, halogen, —CN,—OR_(n1), —NR_(q1)R_(r1), —NR_(n1)COR_(p1), —NR_(n1)CO₂R_(p1), NO₂,—C(O)R_(n1), —C(O)OR_(n1) and —C(O)NR_(q1)R_(r1), wherein any(C₁-C₆)alkyl of Z¹ is optionally substituted with one or more (e.g. 1,2, 3, 4, 5 or 6) halogen;each R_(n1) is independently selected from H and (C₁-C₆)alkyl, whereinany (C₁-C₆)alkyl of R_(n1) is optionally substituted with one or more(e.g. 1, 2, 3, 4, 5 or 6) halogen;each R_(p1) is independently (C₁-C₆)alkyl; andR_(q1) and R_(r1) are each independently selected from H and(C₁-C₆)alkyl or R_(q1) and R_(r1) together with the nitrogen to whichthey are attached form a piperidine, pyrrolidine, morpholine, azetidine,thiomorpholine, piperazine or 4-methylpiperazine.

In another aspect, there is provided a sunless tanning compositioncomprising a compound of formula III:

wherein:

each R¹ is independently H, (C₁-C₆)alkyl, (C₃-C₇)carbocycle orR_(a)C(═O; or the two R¹ groups together form a —(C₃-C₈)alkyl- group, a—(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl- group or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl-group; or

the dashed bonds labeled “a” are absent and the dashed bonds labeled “b”are double bonds; or all the dashed bonds are single bonds;

R² is H, (C₁-C₆)alkyl or aryl, wherein aryl is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

R³ is H, (C₁-C₆)alkyl or aryl, wherein aryl is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

R⁴ is hydroxy, carboxy, (C₁-C₆)alkoxycarbonyl, —OPO₃H₂, —OR_(c), or—NR_(d)R_(e); and R⁵ is H; or R⁴ and R⁵ taken together are oxo;

Y is O, S, NH, P, P(═O) or POH;

Y′ is Si(R_(b))₂ or —Si(R_(b))₂—O—Si(R_(b))₂—;

each R_(a) is independently (C₁-C₆)alkyl, (C₃-C₇)carbocycle or aryl,wherein aryl is optionally substituted with one or more (e.g. 1, 2, 3, 4or 5) Z¹ groups;

each R_(b) is independently (C₁-C₆)alkyl, (C₃-C₇)carbocycle or aryl,wherein aryl is optionally substituted with one or more (e.g. 1, 2, 3, 4or 5) Z¹ groups;

R_(c) is R_(f) or a C₁-C₂₀ saturated or C₂-C₂₀ unsaturated carbon chainthat is optionally substituted with one or more groups independentlyselected from oxo (═O), hydroxy, mercapto, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, NR_(d)R_(e), carboxy, andaryl, wherein aryl is optionally substituted with one or more (e.g. 1,2, 3, 4 or 5) Z¹ groups;

R_(d) is H, (C₁-C₆)alkyl, or (C₁-C₆)alkanoyl;

R_(e) is H or a C₁-C₂₀ saturated or C₂-C₂₀ unsaturated carbon chain thatis optionally substituted with one or more groups independently selectedfrom oxo (═O), hydroxy, mercapto, (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkanoyloxy, NR_(d)R_(e), carboxy, and aryl, wherein aryl isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹groups;

each R_(f), is:

each Z¹ is independently selected from (C₁-C₆)alkyl, halogen, —CN,—OR_(n1), —NR_(q1)R_(r1), —NR_(n1)COR_(p1), —NR_(n1)CO₂R_(p1), NO₂,—C(O)R_(n1), —C(O)OR_(n1) and —C(O)NR_(q1)R_(r1), wherein any(C₁-C₆)alkyl of Z¹ is optionally substituted with one or more (e.g. 1,2, 3, 4, 5 or 6) halogen;

each R_(n1) is independently selected from H and (C₁-C₆)alkyl, whereinany (C₁-C₆)alkyl of R_(n1) is optionally substituted with one or more(e.g. 1, 2, 3, 4, 5 or 6) halogen; each R_(p1) is independently(C₁-C₆)alkyl; and

R_(q1) and R_(r1) are each independently selected from H and(C₁-C₆)alkyl or R_(q1) and R_(r1) together with the nitrogen to whichthey are attached form a piperidine, pyrrolidine, morpholine, azetidine,thiomorpholine, piperazine or 4-methylpiperazine;

or a salt thereof.

In another aspect of the invention, there is provided a compositioncomprising a compound of formula I, II or III for use as a sunlesstanning agent.

In another aspect of the invention, there is provided a method oftanning mammalian skin comprising contacting the skin with an effectiveamount of a compound of formula I, II or III, or a compositioncomprising said compound.

In another aspect of the invention, there is provided a method ofproviding an artificial tan to mammalian skin comprising administeringto said mammal an effective amount of a compound of formula I, II orIII, or a composition comprising said compound.

In another aspect of the invention, there is provided a method ofcoloring mammalian skin, comprising administering to said mammal aneffective amount of a compound of formula I, II or III, or a compositioncomprising said compound.

In another aspect of the invention, there is provided a method ofstimulating pigmentation in mammalian skin, comprising administering tosaid mammal an effective amount of a compound of formula I, II or III,or a composition comprising said compound.

In another aspect of the invention, there is provided a method ofstimulating, or increasing, the production of melanin in melanocytes,comprising contacting said melanocytes with an effective amount of acompound of formula I, II or III, or a composition comprising saidcompound.

DESCRIPTION OF THE FIGURES

FIG. 1. Application on guinea pig skin of 0.025 mL of 600 μM compound117 and positive control Thymidine dinucleotide 5′-phosphate twice dailyfor five consecutive days, a natural DNA component, both demonstratedmarked melanin stimulation by day 15 relative to surrounding untreatedskin.

FIG. 2. Application on guinea pig skin of 0.025 mL of 300 μM compounds10 and 123 twice daily for five consecutive days demonstrated markedmelanin stimulation by day 8 relative to surrounding untreated skin.

DETAILED DESCRIPTION

The following definitions are used, unless otherwise described.

The term “alkyl” as used herein refers to straight and branchedhydrocarbon groups. Reference to an individual radical such as propylembraces only the straight chain radical, a branched chain isomer suchas isopropyl being specifically referred to.

The term “halo” or “halogen” as used herein refers to fluoro, chloro,bromo and iodo.

The term “carbocycle” or “carbocyclyl” refers to a single saturated(i.e., cycloalkyl) or a single partially unsaturated (e.g.,cycloalkenyl, cycloalkadienyl, etc.) ring having 3 to 7 carbon atoms(i.e. (C₃-C₇)carbocycle). The term “carbocycle” or “carbocyclyl” alsoincludes multiple condensed ring systems (e.g. ring systems comprising2, 3 or 4 carbocyclic rings). Accordingly, carbocycle includesmulticyclic carbocycles having 7 to 12 carbon atoms as a bicycle, and upto about 20 carbon atoms as a polycycle. Multicyclic carbocycles can beconnected to each other via a single carbon atom to form a spiroconnection (e.g. spiropentane, spiro[4,5]decane, spiro[4.5]decane,etc.), via two adjacent carbon atoms to form a fused connection such asa bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atomsarranged as a bicyclo [5,6] or [6,6] system (e.g. decahydronaphthalene,norsabinane, norcarane) or via two non-adjacent carbon atoms to form abridged connection (e.g. norbornane, bicyclo[2.2.2]octane, etc.). The“carbocycle” or “carbocyclyl” may also be optionally substituted withone or more (e.g. 1, 2 or 3) oxo groups. Non-limiting examples ofmonocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl and cycloheptyl.

The term “aryl” as used herein refers to a single aromatic ring or amultiple condensed ring system. For example, an aryl group can have 6 to20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Arylincludes a phenyl radical. Aryl also includes multiple condensed ringsystems (e.g. ring systems comprising 2, 3 or 4 rings) having about 9 to20 carbon atoms in which at least one ring is aromatic. Such multiplecondensed ring systems may be optionally substituted with one or more(e.g. 1, 2 or 3) oxo groups on any carbocycle portion of the multiplecondensed ring system. It is to be understood that the point ofattachment of a multiple condensed ring system, as defined above, can beat any position of the ring system including an aryl or a carbocycleportion of the ring. Typical aryl groups include, but are not limitedto, phenyl, indenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl,anthracenyl, and the like.

The term “effective amount” as used herein refers to the amount of thecompound or composition that causes skin to darken or tan or otherwisecause a color change in skin.

It will be appreciated by those skilled in the art that compounds of theinvention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, orstereoisomeric form, or mixtures thereof, of a compound of theinvention, which possess the useful properties described herein, itbeing well known in the art how to prepare optically active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase.

Specific values listed below for radicals, substituents, and ranges, arefor illustration only; they do not exclude other defined values or othervalues within defined ranges for the radicals and substituents. Specificvalues listed are values for compounds of formula I and II as well asall sub-formulas of formula I (e.g. formulas Ia, Ib Ic, Id, Ie, Ifetc.).

It has been determined that the compounds of formula I, II and III causea darkening of skin. Accordingly, the invention provides a method fortanning mammalian skin comprising contacting the skin with an effectiveamount of a compound of formula I, II or III or a composition containingsuch compound. In another aspect, there is provided a method ofproviding an artificial tan to mammalian skin comprising contacting theskin with an effective amount of a compound of formula I, II or III or acomposition containing such compound. In a particular embodiment, thecomposition is sprayed on to the subject in a tanning booth. In anotheraspect, there is provided a method of coloring mammalian skin,comprising contacting the skin with an effective amount of a compound offormula I, II or III or a composition containing such compound. Inanother aspect of the invention, there is provided a method ofstimulating pigmentation in mammalian skin, comprising contacting theskin with an effective amount of a compound of formula I, II or III, ora composition comprising said compound. In another aspect of theinvention, there is provided a method of stimulating the production ofmelanin in melanocytes, comprising contacting said melanocytes with aneffective amount of a compound of formula I, II or III, or a compositioncomprising said compound. In particular embodiments, the foregoingmethods involve applying the compounds and compositions topically tohuman skin. In particular embodiments, the foregoing methods involveapplying the compounds and compositions topically to human skin in anaerosol formulation. In particular embodiments, the foregoing methodsinvolve administering the compounds and compositions orally.

The ability of a compound or composition of the invention to darkenanimal skin may be determined using pharmacological models which arewell known to the art. For example, compounds 3a, 10, 24a (5%) in creamvehicle was applied topically to guinea pig dorsal skin which wasobserved for darkening over the course of several days or weeks.

A specific group of compounds of formula I used in sunless tanningcompositions of the invention are compounds of formula Ia:

wherein X is a —(C₃-C₅)alkyl- group or a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl-group or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; or a salt thereof.

Another specific group of compounds of formula I used in sunless tanningcompositions of the invention are compounds of formula Ib:

wherein X is a —(C₃-C₈)alkyl- group or a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl-group or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; or a salt thereof.

Another specific group of compounds of formula I used in sunless tanningcompositions of the invention are compounds of formula Ic:

wherein X is a —(C₃-C₈)alkyl- group or a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl-group or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; or a salt thereof.

Another specific group of compounds of formula I used in sunless tanningcompositions of the invention are compounds of formula Id:

wherein X is a —(C₃-C₈)alkyl- group or a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl-group or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; or a salt thereof.

Another specific group of compounds of formula I used in sunless tanningcompositions of the invention are compounds of formula Ie:

wherein each X is independently a —(C₃-C₈)alkyl- group or a—(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl-group or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl-group; or a salt thereof.

Another specific group of compounds of formula I used in sunless tanningcompositions of the invention are compounds of formula If:

wherein each X is independently a —(C₃-C₅)alkyl- group or a—(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl- group or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl-group; or a salt thereof.

Specifically, (C₁-C₆)alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl or hexyl.

Specifically, (C₃-C₇)carbocycle can be cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and partially unsaturatedderivatives thereof.

A specific value for R¹ is H.

A specific value for X is —(C₃-C₈)alkyl- or—(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl-.

Another specific value for X is —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl-.

A specific group of compounds of formula I are compounds wherein each R¹is independently H or (C₁-C₆)alkyl, and the two R⁴ groups together forma —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl- group.

A specific group of compounds of formula I are compounds wherein R¹ is Hand X is —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl-; or R¹ is (C₁-C₆)alkyl,(C₃-C₇)carbocycle, aryl or R_(a)C(═O)—; and X is —(C₃-C₈)alkyl- or—(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl.

A specific value for Y is NH.

A specific group of compounds of formula I are compounds wherein R² andR³ are each independently (C₁-C₆)alkyl.

A specific group of compounds of formula I are compounds wherein R² andR³ are each methyl.

A specific compound of formula I used in sunless tanning compositions ofthe invention is:

or a salt thereof.

In one embodiment of the invention the compounds of formula I are otherthan:

In another embodiment of the invention the compounds of formula I areother than:

wherein each R^(2a) is methyl or each R^(2a) is ethyl; and n is 3-6.

A specific group of compounds used in sunless tanning compositions ofthe invention are compounds of formula I wherein:

each R¹ is independently H, (C₁-C₆)alkyl, (C₃-C₇)carbocycle orR_(a)C(═O)—, and the two R⁴ groups together form a —(C₃-C₈)alkyl- group,a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl- group or a—(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; or

each R⁴ is independently H, (C₁-C₆)alkyl, (C₃-C₇)carbocycle orR_(a)C(═O)—, and the two R¹ groups together form a —(C₃-C₈)alkyl- group,a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl- group or a—(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; or

the two R⁴ groups together form a —(C₃-C₈)alkyl- group, a—(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl group or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl-group and the two R¹ groups together form a —(C₃-C₈)alkyl- group, a—(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl- group or a—(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl-group;

the dashed bonds labeled “a” are absent and the dashed bonds labeled “b”are double bonds; or all the dashed bonds are single bonds;

R² is H, (C₁-C₆)alkyl or aryl, wherein aryl is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

R³ is H, (C₁-C₆)alkyl or aryl, wherein aryl is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

Y is O, S, NH, P, P(═O) or POH;

Y′ is Si(R_(b))₂ or —Si(R_(b))₂—O—Si(R_(b))₂—;

each R_(a) is independently (C₁-C₆)alkyl, (C₃-C₇)carbocycle or aryl,wherein aryl is optionally substituted with one or more (e.g. 1, 2, 3, 4or 5) Z¹ groups;

each R_(b) is independently (C₁-C₆)alkyl, (C₃-C₇)carbocycle or aryl,wherein aryl is optionally substituted with one or more (e.g. 1, 2, 3, 4or 5) Z¹ groups; and

each Z¹ is independently selected from (C₁-C₆)alkyl, halogen, —CN,—OR_(n1), —NR_(q1)R_(r1), —NR_(n1)COR_(p1), —NR_(n1)CO₂R_(p1), NO₂,—C(O)R_(n1), —C(O)OR_(n1) and —C(O)NR_(q1)R_(r1), wherein any(C₁-C₆)alkyl of Z¹ is optionally substituted with one or more (e.g. 1,2, 3, 4, 5 or 6) halogen;

each R_(n1) is independently selected from H and (C₁-C₆)alkyl, whereinany (C₁-C₆)alkyl of R_(n1) is optionally substituted with one or more(e.g. 1, 2, 3, 4, 5 or 6) halogen;

each R_(p1) is independently (C₁-C₆)alkyl; and

R_(q1) and R_(r1) are each independently selected from H and(C₁-C₆)alkyl or R_(q1) and R_(r1) together with the nitrogen to whichthey are attached form a piperidine, pyrrolidine, morpholine, azetidine,thiomorpholine, piperazine or 4-methylpiperazine;

and salts thereof.

A specific compound used in sunless tanning compositions of theinvention is a compound selected from the group consisting of:

and salts thereof.

A specific R_(c) is selected from butanoyl, hexadecanoyl, octadecanoyl,benzoyl, 3-phenylprop-2-enoyl, 3-(4-methoxyphenyl)prop-2-enoyl,3-carboxy-3-hydroxypropanoyl, 2-(N-acetylamino)-3-mercaptopropanoyl,4-(4-methoxy-3-sulfobenzoyl)benzoyl,4-(3-(4-methoxyphenyl)-1,3-dioxopropyl)benzoyl, and

A specific compound used in sunless tanning compositions of theinvention is a compound selected from the group consisting of:

and salts thereof.

A specific compound used in sunless tanning compositions of theinvention is a compound selected from the group consisting of:

and salts thereof.

Processes for preparing compounds of formula I and II are provided asfurther embodiments of the invention and are illustrated in Schemes 1and 2.

wherein X is —(C₃-C₈)alkyl- or —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl- or a—(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl-group and all other variables have thevalues as described herein.

wherein X is —(C₃-C₈)alkyl- or —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl- or a—(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl-group and all other variables have thevalues as described herein.

Accordingly, the invention also provides a sunless tanning compositioncomprising a compound of formula II:

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier,

wherein:

R¹ is H, (C₁-C₆)alkyl, (C₃-C₇)carbocycle or R_(a)C(═O)—;

R² is H, (C₁-C₆)alkyl or aryl, wherein aryl is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

R⁴ is H, (C₁-C₁₀)alkyl, (C₃-C₇)carbocycle or R_(a)C(═O)—;

R_(a) is or (C₁-C₆)alkyl, (C₃-C₇)carbocycle or aryl, wherein aryl isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹groups;

each Z¹ is independently selected from (C₁-C₆)alkyl, halogen, —CN,—OR_(n1), —NR_(q1)R_(r1), —NR_(n1)COR_(p1), —NR_(n1)CO₂R_(p1), NO₂,—C(O)R_(n1), —C(O)OR_(n1) and —C(O)NR_(q1)R_(r1), wherein any(C₁-C₆)alkyl of Z¹ is optionally substituted with one or more (e.g. 1,2, 3, 4, 5 or 6) halogen;

each R_(n1) is independently selected from H and (C₁-C₆)alkyl, whereinany (C₁-C₆)alkyl of R_(n1) is optionally substituted with one or more(e.g. 1, 2, 3, 4, 5 or 6) halogen;

each R_(p1) is independently (C₁-C₆)alkyl; and

R_(q1) and R_(n1) are each independently selected from H and(C₁-C₆)alkyl or R_(q1) and R_(r1) together with the nitrogen to whichthey are attached form a piperidine, pyrrolidine, morpholine, azetidine,thiomorpholine, piperazine or 4-methylpiperazine.

In another aspect of the invention, sunless tanning compositions of theinvention comprise a compound of formula III:

wherein:

each R¹ is independently H, (C₁-C₆)alkyl, (C₃-C₇)carbocycle orR_(a)C(═O; or the two R¹ groups together form a —(C₃-C₈)alkyl- group, a—(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl- group or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl-group; or

-   -   the dashed bonds labeled “a” are absent and the dashed bonds        labeled “b” are double bonds; or all the dashed bonds are single        bonds;    -   R² is H, (C₁-C₆)alkyl or aryl, wherein aryl is optionally        substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;    -   R³ is H, (C₁-C₆)alkyl or aryl, wherein aryl is optionally        substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;    -   R⁴ is hydroxy, carboxy, (C₁-C₆)alkoxycarbonyl, —OPO₃H₂, —OR_(c),        or —NR_(d)R_(e); and R⁵ is H; or R⁴ and R⁵ taken together are        oxo;

Y is O, S, NH, P, P(═O) or POH;

Y′ is Si(R_(b))₂ or —Si(R_(b))₂—O—Si(R_(b))₂—;

each R_(a) is independently (C₁-C₆)alkyl, (C₃-C₇)carbocycle or aryl,wherein aryl is optionally substituted with one or more (e.g. 1, 2, 3, 4or 5) Z¹ groups;

each R_(b) is independently (C₁-C₆)alkyl, (C₃-C₇)carbocycle or aryl,wherein aryl is optionally substituted with one or more (e.g. 1, 2, 3, 4or 5) Z¹ groups;

R_(c) is R_(f) or a C₁-C₂₀ saturated or C₂-C₂₀ unsaturated carbon chainthat is optionally substituted with one or more groups independentlyselected from oxo (═O), hydroxy, mercapto, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, NR_(d)R_(e), carboxy, andaryl, wherein aryl is optionally substituted with one or more (e.g. 1,2, 3, 4 or 5) Z¹ groups;

R_(d) is H, (C₁-C₆)alkyl, or (C₁-C₆)alkanoyl;

R_(e) is H or a C₁-C₂₀ saturated or C₂-C₂₀ unsaturated carbon chain thatis optionally substituted with one or more groups independently selectedfrom oxo (═O), hydroxy, mercapto, (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkanoyloxy, NR_(d)R_(e), carboxy, and aryl, wherein aryl isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹groups;

each R_(f), is:

each Z¹ is independently selected from (C₁-C₆)alkyl, halogen, —CN,—OR₁₁, —NR_(q)R_(r), —NR_(n1)COR_(p1), —NR_(n1)CO₂R_(p1), NO₂,—C(O)R_(n1), —C(O)OR_(n1) and —C(O)NR_(q1)R_(r1), wherein any(C₁-C₆)alkyl of Z¹ is optionally substituted with one or more (e.g. 1,2, 3, 4, 5 or 6) halogen;

each R_(n1) is independently selected from H and (C₁-C₆)alkyl, whereinany (C₁-C₆)alkyl of R_(n1) is optionally substituted with one or more(e.g. 1, 2, 3, 4, 5 or 6) halogen;

each R_(p1) is independently (C₁-C₆)alkyl; and

R_(q1) and R_(r1) are each independently selected from H and(C₁-C₆)alkyl or R_(q1) and R_(r1) together with the nitrogen to whichthey are attached form a piperidine, pyrrolidine, morpholine, azetidine,thiomorpholine, piperazine or 4-methylpiperazine;

or a salt thereof.

A specific group of compounds of formula III are compounds of formulaIIIa:

and salts thereof.

A specific group of compounds of formula III are compounds of formulaIIIb:

and salts thereof.

A specific value for R¹ is independently H or (C₁-C₆)alkyl.

A specific value for Y is NH.

A specific value for R¹ is H.

Specifically R² and R³ can each independently be (C₁-C₆)alkyl.

A specific value for R⁴ is hydroxyl.

A specific value for R⁴ is carboxy.

A specific value for R⁴ is (C₁-C₆)alkoxycarbonyl.

A specific value for R⁴ is —OPO₃H₂.

A specific value for R⁴ is —OR_(c).

A specific value for R⁴ is —NR_(d)R_(e).

A specific value for R_(c) is a C₁-C₂₀ saturated or C₂-C₂₀ unsaturatedalkanoyl group that is optionally substituted with one or more groupsindependently selected from oxo (═O), hydroxy, mercapto, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, NR_(d)R_(e), carboxy, andaryl.

A specific value for R_(c) is a C₁-C₂₀ saturated or C₂-C₂₀ unsaturatedalkanoyl group that is optionally substituted with one or more groupsindependently selected from oxo (═O), hydroxy, mercapto, carboxy, andaryl, and R_(f),

A specific value for R_(c) is R_(f),

A specific value for R_(c) is butanoyl, hexadecanoyl, octadecanoyl,benzoyl, 3-phenylprop-2-enoyl, or 3-(4-methoxyphenyl)prop-2-enoyl.

A specific value for R_(e) is H or a C₁-C₂₀ saturated or C₂-C₂₀unsaturated alkanoyl group that is optionally substituted with one ormore groups independently selected from oxo (═O), hydroxy, mercapto,(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, NR_(d)R_(e),carboxy, and aryl.

A specific value for R_(e) is a C₁-C₂₀ saturated or C₂-C₂₀ unsaturatedalkanoyl group that is optionally substituted with one or more groupsindependently selected from oxo (═O), hydroxy, mercapto, carboxy, andaryl, and R_(f),

A specific value for R_(e) is butanoyl, hexadecanoyl, octadecanoyl,benzoyl, 3-phenylprop-2-enoyl, or 3-(4-methoxyphenyl)prop-2-enoyl.

-   -   A specific compound is a compound which

and salts thereof.

A specific compound is a compound which is selected from:

and salts thereof. Specific salts include salts withN,N-dimethylaminoethanol or glucosamine.

Processes for preparing compounds of formula I are provided as furtherembodiments of the invention and are illustrated in Schemes 3 and 4.

The invention also provides a sunless tanning composition comprising amixture of two or more compounds of formula I and/or formula II (asdescribed above), or salts thereof, and a carrier.

The invention also provides processes and intermediates disclosed hereinthat are useful for preparing compounds of formula II (as describedabove) or salts thereof.

In cases where compounds are sufficiently basic or acidic, a salt of acompound of the formula can be useful as an intermediate for isolatingor purifying a compound of formula I or formula II. Additionally,administration of a compound of formula I or formula II as apharmaceutically or dermatologically acceptable acid or base salt may beappropriate. Examples of pharmaceutically acceptable salts includingdermatologically acceptable salts are organic acid addition salts formedwith acids which form a physiological acceptable anion, for example,tosylate, methanesulfonate, acetate, citrate, malonate, tartrate,succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate.Suitable inorganic salts may also be formed, including hydrochloride,sulfate, nitrate, bicarbonate, and carbonate salts.

Pharmaceutically acceptable salts which include dermatologicallyacceptable salts may be obtained using standard procedures well known inthe art, for example by reacting a sufficiently basic compound such asan amine with a suitable acid affording a physiologically acceptableanion. Alkali metal (for example, sodium, potassium or lithium) oralkaline earth metal (for example calcium) salts of carboxylic acids canalso be made.

The compounds of formula I or formula II can be formulated as sunlesstanning compositions and administered to a mammalian host, such as ahuman patient in a variety of forms adapted to the chosen route ofadministration, i.e., orally or parenterally, by intravenous,intramuscular, topical or subcutaneous routes. It is to be understoodthat the term pharmaceutically acceptable carrier also includes carriersthat are suitable for topical use as described herein below. In oneembodiment of the invention the pharmaceutically acceptable carrier is adermatologically acceptable carrier.

Thus, the present compounds may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle suchas an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets, or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The compound may also be administered intravenously or intraperitoneallyby infusion or injection. Solutions of the compound or its salts can beprepared in water, optionally mixed with a nontoxic surfactant.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols, triacetin, and mixtures thereof and in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In an embodiment it will includeisotonic agents, for example, sugars, buffers or sodium chloride.Prolonged absorption of the injectable compositions can be brought aboutby the use in the compositions of agents delaying absorption, forexample, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the compoundin the required amount in the appropriate solvent with various otheringredients enumerated above, as required, followed by filtersterilization. In the case of sterile powders for the preparation ofsterile injectable solutions, a particular method of preparation isvacuum drying and the freeze drying techniques, which yield a powder ofthe active ingredient plus any additional desired ingredient present inthe previously sterile-filtered solutions.

The amount of the compound, or an active salt or derivative thereof,required for use in treatment will vary not only with the particularsalt selected but also with the route of administration, the nature ofthe condition being treated and the age and condition of the patient andwill be ultimately at the discretion of the attendant physician orclinician.

In general, however, a suitable dose will be in the range of from about0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of bodyweight per day, such as 3 to about 50 mg per kilogram body weight of therecipient per day, for example, in the range of 6 to 90 mg/kg/day, suchas in the range of 15 to 60 mg/kg/day.

The compound may be formulated in unit dosage form; for example,containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently,50 to 500 mg of active ingredient per unit dosage form. In oneembodiment, the invention provides a composition comprising a compoundof the invention formulated in such a unit dosage form.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

The compounds of formula I or formula II can be formulated asdermatological compositions and applied to a mammalian host, such as ahuman by a topical route. For topical administration, the presentcompounds may be applied in pure form, i.e., when they are liquids.However, it will generally be desirable to administer them to the skinas compositions or formulations, in combination with a dermatologicallyacceptable carrier, which may be a solid carrier or a liquid carrier.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina, cyclodextrins and the like.Useful liquid carriers include water, alcohols or glycols orwater-alcohol/glycol blends, in which the present compounds can bedissolved or dispersed at effective levels, optionally with the aid ofnon-toxic surfactants. Additional carriers include vegetable oils,hydrocarbon oils and waxes, silicone oils, animal and marine fats oroils. Adjuvants such as fragrances and additional antimicrobial agentscan be added to the composition to optimize the properties for a givenuse. Thickeners such as synthetic polymers, fatty acids, fatty acidsalts and esters, fatty alcohols, modified celluloses or modifiedmineral materials can also be employed with liquid carriers to formspreadable pastes, gels, ointments, soaps, and the like, for applicationdirectly to the skin of the user. Cosmetic compositions, may containconventional ingredients known to those of ordinary skill in the art,such as those described in Kirk-Othmer, Encyclopedia of ChemicalTechnology, Third Edition (1979), Vol. 7, pages 143-176. Specificingredients, including typical sunscreens, are listed in, for example,the above mentioned Kirk-Othmer Encyclopedia, at pages 153-154. Inaddition, topical preparations and cosmetic formulations may be preparedas described in U.S. Pat. Nos. 4,199,576, 4,136,165, and 4,248,861.Examples of additional useful dermatological compositions which can beused to deliver the compounds of the invention to the skin are known tothe art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392),Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157)and Wortzman (U.S. Pat. No. 4,820,508).

The percentage of the components of the compositions and preparationsmay be varied. In general, a suitable dermatological composition of theinvention will typically comprise a compound of formula I or formula IIor a mixture thereof in an effective amount and may be between about0.01-25% of the weight of a dermatological composition. In anembodiment, the amount of the sunless tanning compound in suchdermatological compositions is from about 2% to about 12% by weight. Inan embodiment, the amount of the sunless tanning compound in suchdermatological compositions is about 5% by weight.

The compounds of formula I and formula II and dermatologicalcompositions thereof as described herein can be used in sunscreens orother cosmetic formulations containing compounds that protect skin orDNA in skin from photodamage or repair photodamaged skin or photodamagedDNA in the skin. It is apparent to those of ordinary skill in the artthat the compositions or formulations can be in many forms, including,but not limited to, for example, solutions, lotions, oils, sprays,creams, pastes, emulsions, sprays, or aerosols and delivered in asuitable manner.

Compositions of the invention may be formulated as sunscreen or suntanlotion formulations by combining with sun screening agents such asavobenzone, ecamsule, methylanthranilate, oxybenzone, dioxybenzone,sulisobenzone, octinoxate, homosalate, octocrylene and octylsalate. Suchcompositions may comprise organic UV filters, so-called hydrophilic orlipophilic sun-protection filters, which are effective in the UVA regionand/or UVB region and (/or IR and/or VIS region (absorbers). Thesesubstances can be selected, in particular, from cinnamic acidderivatives, salicylic acid derivatives, camphor derivatives, triazinederivatives, β,β-diphenylacrylate derivatives, p-aminobenzoic acidderivatives and polymeric filters and silicone filters, which aredescribed in the WO93/04665. Further examples of organic filters areindicated in patent application EP-A 0 487 404. Particularly suitablefor a combination are: para-aminobenzoic acid and derivatives thereof:PABA, Ethyl PABA, Ethyl dihydroxypropyl PABA, Ethylhexyl dimethyl PABA,for example marketed by ISP under the name “Escalol 507”, Glyceryl PABA,PEG-25 PABA, for example marketed under the name “Uvinul P25” by BASF.

Other UV filter ingredients which may be incorporated in compositions ofthe invention include:

-   -   Salicylates: Homosalate marketed by Merck under the name        “Eusolex HMS”; Ethylhexyl salicylate, for example marketed by        Symrise under the name “Neo Heliopan OS”, Dipropylene glycol        salicylate, for example marketed by Scher under the name        “Dipsal”, TEA salicylate, for example marketed by Symrise under        the name “Neo Heliopan TS”.    -   β,β-Diphenylacrylate derivatives: Octocrylene, for example        marketed by Merck under the name “Eusolex® OCR”, “Uvinul N539”        from BASF, Etocrylene, for example marketed by BASF under the        name “Uvinul N35”.    -   Benzophenone derivatives: Benzophenone-1, for example marketed        under the name “Uvinul 400”; Benzophenone-2, for example        marketed under the name “Uvinul D50”; Benzophenone-3 or        Oxybenzone, for example marketed under the name “Uvinul M40”;        Benzophenone-4, for example marketed under the name “Uvinul        MS40”; Benzophenone-9, for example marketed by BASF under the        name “Uvinul DS-49”, Benzophenone-5, Benzophenone-6, for example        marketed by Norquay under the name “Helisorb 11”,        Benzophenone-8, for example marketed by American Cyanamid under        the name “Spectra-Sorb UV-24”, Benzophenone-12 n-hexyl        2-(4-diethylamino-2-hydroxybenzoyl)benzoate or        2-hydroxy-4-methoxybenzophenone, marketed by Merck, Darmstadt,        under the name Eusolex® 4360.    -   Benzylidenecamphor derivatives: 3-Benzylidenecamphor, for        example marketed by Chimex under the name “Mexoryl SD”,        4-Methylbenzylidenecamphor, for example marketed by Merck under        the name “Eusolex 6300”, benzylidenecamphorsulfonic acid, for        example marketed by Chimex under the name “Mexoryl SL”, Camphor        benzalkonium methosulfate, for example marketed by Chimex under        the name “Mexoryl SO”, terephthalylidenedicamphorsulfonic acid,        for example marketed by Chimex under the name “Mexoryl SX”,        Polyacrylamidomethylbenzylidenecamphor marketed by Chimex under        the name “Mexoryl SW”.    -   Phenylbenzimidazole derivatives: phenylbenzimidazolesulfonic        acid, for example marketed by Merck under the name “Eusolex        232”, disodium phenyl dibenzimidazole tetrasulfonate, for        example marketed by Symrise under the name “Neo Heliopan AP”.    -   Phenylbenzotriazole derivatives: Drometrizole trisiloxane, for        example marketed by Rhodia Chimie under the name “Silatrizole”,    -   Methylenebis(benzotriazolyl)tetramethylbutylphenol in solid        form, for example marketed by Fairmount Chemical under the name        “MIXXIM BB/100”, or in micronized form as an aqueous dispersion,        for example marketed by BASF under the name “Tinosorb M”.    -   Triazine derivatives: ethylhexyltriazone, for example marketed        under the name “Uvinul T150” by BASF,        diethylhexylbutamidotriazone, for example marketed under the        name “Uvasorb HEB” by Sigma 3V, 2,4,6-tris(diisobutyl        4′-aminobenzalmalonate)-s-triazine or        2,4,6-tris(biphenyl)-1,3,5-triazine. marketed as Tinosorb A2B by        BASF,        2,2′-[6-(4-methoxyphenyl)-1,3,5-triazine-2,4-diyl]bis[5-(2-ethylhexyl)oxy]phenol,        marketed as Tinosorb S by BASF,        N2,N4-bis[4-[5-(1,1-dimethylpropyl)-2-benzoxazolyl]phenyl]-N-6-(2-ethylhexyl)-1,3,5-triazine-2,4,6-triamine        marketed as Uvasorb K 2A by Sigma 3V.    -   Anthraniline derivatives: Menthyl anthranilate, for example        marketed by Symrise under the name “Neo Heliopan MA”.    -   Imidazole derivatives:        Ethylhexyldimethoxybenzylidenedioxoimidazoline propionate.    -   Benzalmalonate derivatives: polyorganosiloxanes containing        functional benzalmalonate groups, such as, for example,        polysilicone-15, for example marketed by Hoffmann LaRoche under        the name “Parsol SLX”.    -   4,4-Diarylbutadiene derivatives:        1,1-Dicarboxy(2,2′-dimethylpropyl)-4,4-diphenylbutadiene.    -   Benzoxazole derivatives:        2,4-bis[5-(1-dimethylpropyl)benzoxazol-2-yl(4-phenyl)        imino]-6-(2-ethylhexyl)imino-1,3,5-triazine, for example        marketed by Sigma 3V under the name Uvasorb K2A, and mixtures        comprising this.

Suitable organic UV-protecting substances can preferably be selectedfrom: Ethylhexyl salicylate, Phenylbenzimidazolesulfonic acid,Benzophenone-3, Benzophenone-4, Benzophenone-5, n-Hexyl2-(4-diethylamino-2-hydroxybenzoyl)benzoate, 4-Methylbenzylidenecamphor,Terephthalylidenedicamphorsulfonic acid, Disodiumphenyldibenzimidazoletetrasulfonate,Methylenebis(benzotriazolyl)tetramethylbutylphenol, Ethylhexyl Triazone,Diethylhexyl Butamido Triazone, Drometrizole trisiloxane,Polysilicone-15,1,1-Dicarboxy(2,2′-dimethylpropyl)-4,4-diphenylbutadiene,2,4-bis[5-1 (dimethylpropyl)benzoxazol-2-yl(4-phenyl)imino]-6-(2-ethylhexyl)imino-1,3,5-triazine and mixtures thereof. Theseorganic UV filters are generally incorporated into formulations in anamount of 0.01 percent by weight to 20 percent by weight, preferably 1%by weight-10% by weight.

The compositions of the invention may comprise further inorganic UVfilters, so-called particulate UV filters. These combinations withparticulate UV filters are possible both as powder and also asdispersion or paste. In an embodiment the inorganic UV filter is atitanium dioxide, such as, for example, coated titanium dioxide (forexample Eusolex® T-2000, Eusolex® T-AQUA, Eusolex® T-AVO, Eusolex®T-OLEO), a zinc oxide (for example Sachtotec), an iron oxide or a ceriumoxide and/or zirconium oxide. Furthermore, combinations with pigmentarytitanium dioxide or zinc oxide are also possible, where the particlesize of these pigments are greater than or equal to 200 nm, for exampleHombitan® FG or Hombitan® FFPharma.

Compositions of the invention may comprise inorganic UV filters whichhave been aftertreated by conventional methods, as described, forexample, in Cosmetics & Toiletries, 1990, 105, 53-64. One or more of thefollowing aftertreatment components can be: amino acids, beeswax, fattyacids, fatty acid alcohols, anionic surfactants, lecithin,phospholipids, sodium, potassium, zinc, iron or aluminium salts of fattyacids, polyethylenes, silicones, proteins (particularly collagen orelastin), alkanolamines, silicon dioxide, aluminium oxide, further metaloxides, phosphates, such as sodium hexametaphosphate, or glycerine.

In an embodiment, particulate UV filters used in compositions of theinvention are:

-   -   untreated titanium dioxides, such as, the products Microtitanium        Dioxide MT 500 B from Tayca; titanium dioxide P25 from Degussa,    -   aftertreated micronized titanium dioxides with aluminium oxide        and silicon dioxide aftertreatment, such as, the product        “Microtitanium Dioxide MT 100 SA from Tayca; or the product        “Tioveil Fin” from Uniqema,    -   aftertreated micronized titanium dioxides with aluminium oxide        and/or aluminium stearate/laurate aftertreatment, such as,        Microtitanium Dioxide MT 100 T from Tayca, Eusolex T-2000 from        Merck,    -   aftertreated micronized titanium dioxides with iron oxide and/or        iron stearate aftertreatment, such as, the product        “Microtitanium Dioxide MT 100 F” from Tayca,    -   aftertreated micronized titanium dioxides with silicon dioxide,        aluminium oxide and silicone aftertreatment, such as, the        product “Microtitanium Dioxide MT 100 SAS”, from Tayca,    -   aftertreated micronized titanium dioxides with sodium        hexametaphosphates, such as, the product “Microtitanium Dioxide        MT 150 W” from Tayca.

The treated micronized titanium dioxides employed for the combinationmay also be aftertreated with:

-   -   octyltrimethoxysilanes; such as, the product Tego Sun T 805 from        Evonik Goldschmidt GmbH,    -   silicon dioxide; such as, for example, the product Parsol T-X        from DSM,    -   aluminium oxide and stearic acid; such as, the product UV-Titan        M160 from Sachtleben,    -   aluminium and glycerine; such as, the product UV-Titan from        Sachtleben,    -   aluminium and silicone oils, such as, the product UV-Titan M262        from Sachtleben,    -   sodium hexametaphosphate and polyvinylpyrrolidone,    -   polydimethylsiloxanes, such as, the product 70250 Cardre UF        TiO2SI3” from Cardre,    -   polydimethylhydrogenosiloxanes, such as, for example, the        product Microtitanium Dioxide USP Grade Hydrophobic” from Color        Techniques.

In a particular embodiment, compositions of the invention may includeuntreated zinc oxides, such as, the product Z-Cote from BASF (Sunsmart),Nanox from Elementis. In another particular embodiment, compositions ofthe invention may include aftertreated zinc oxides, such as, thefollowing products:

-   -   “Zinc Oxide CS-5” from Toshibi (ZnO aftertreated with        polymethylhydrogeno-siloxanes);    -   Nanogard Zinc Oxide FN from Nanophase Technologies;    -   “SPD-Z1” from Shin-Etsu (ZnO aftertreated with a        silicone-grafted acrylic polymer, dispersed in        cyclodimethylsiloxanes;    -   “Escalol Z100” from ISP (aluminium oxide-aftertreated ZnO        dispersed in an ethylhexyl        methoxycinnamate/PVP-hexadecene/methicone copolymer mixture);        and    -   “Fuji ZNO-SMS-10” from Fuji Pigment (ZnO aftertreated with        silicon dioxide and polymethylsilesquioxane).

In another particular embodiment, compositions of the invention mayinclude untreated cerium oxide micropigment, for example with the name“Colloidal Cerium Oxide” from Rhone Poulenc. In another particularembodiment, compositions of the invention may include untreated and/oraftertreated iron oxides with the name Nanogar from Arnaud.

By way of example, it is also possible to employ mixtures of variousmetal oxides, such as, for example, titanium dioxide and cerium oxide,with and without aftertreatment, such as, for example, the productSunveil A from Ikeda. In addition, mixtures of aluminium oxide, silicondioxide and silicone-aftertreated titanium dioxide, zinc oxide mixtures,such as, the product UV-Titan M261 from Sachtleben, can also be used incombination with the UV protection agents according to the invention.

Inorganic UV filters are generally incorporated into the preparations inan amount of 0.1 percent by weight to 25 percent by weight, preferably2% by weight-10% by weight.

By combination of one or more of the said compounds having a UV filteraction, the protective action against harmful effects of the UVradiation can be optimized.

All said UV filters can also be employed in encapsulated form. Inparticular, it is advantageous to employ organic UV filters inencapsulated form. The capsules in preparations to be employed inaccordance with the invention are preferably present in amounts whichensure that the encapsulated UV filters are present in the preparationin the percent by weight ratios indicated above.

Particular compositions of the invention comprise at least one furthercosmetic active compound, for example selected from antioxidants,anti-ageing compounds, anti-wrinkle, anti-flake, anti-acne, deodorants,anti-cellulite compounds and vitamins. Antioxidants include amino acids(for example glycine, histidine, tyrosine, tryptophan) and derivativesthereof, imidazoles, (for ecample urocanic acid) and derivativesthereof, peptides, such as D,L-carnosine, D-carnosine, L-carnosine andderivatives thereof (for example anserine), carotinoids, carotenes (forexample α-carotene, β-carotene, lycopene) and derivatives thereof,chlorogenic acid and derivatives thereof, lipoic acid and derivativesthereof (for example dihydrolipoic acid), aurothioglucose,propylthiouracil and other thiols (for example thioredoxin, glutathione,cysteine, cystine, cystamine and the glycosyl, N-acetyl, methyl, ethyl,propyl, amyl, butyl and lauryl, palmitoyl, oleyl, γ-linoleyl,cholesteryl and glyceryl esters thereof) and salts thereof, dilaurylthiodipropionate, distearyl thiodipropionate, thiodipropionic acid andderivatives thereof (esters, ethers, peptides, lipids, nucleotides,nucleosides and salts), and sulfoximine compounds (for examplebuthionine sulfoximines, homocysteine sulfoximine, buthionine sulfones,penta-, hexa- and heptathionine sulfoximine) in very low tolerated doses(for example pmol to mmol/kg), and also (metal) chelating agents, (forexample α-hydroxyfatty acids, palmitic acid, phytic acid, lactoferrin),α-hydroxy acids (for example citric acid, lactic acid, malic acid),humic acid, bile acid, bile extracts, bilirubin, biliverdin, EDTA, EGTAand derivatives thereof, unsaturated fatty acids and derivativesthereof, vitamin C and derivatives (for example ascorbyl palmitate,magnesium ascorbyl phosphate, ascorbyl acetate), tocopherols andderivatives (for example vitamin E acetate), vitamin A and derivatives(for example vitamin A palmitate) and coniferyl benzoate of benzoinresin, rutinic acid and derivatives thereof, a-glycosylrutin, ferulicacid, furfurylideneglucitol, carnosine, butylhydroxytoluene,butylhydroxyanisole, nordihydroguaiaretic acid, trihydroxybutyrophenone,quercetin, uric acid and derivatives thereof, mannose and derivativesthereof, zinc and derivatives thereof (for example ZnO, ZnSO₄), seleniumand derivatives thereof (for example selenomethionine), stilbenes andderivatives thereof (for example stilbene oxide, trans-stilbene oxide).

Mixtures of antioxidants are likewise suitable for use in thecompositions of the invention. Available mixtures are, for example,mixtures comprising, as active ingredients, lecithin, L-(+)-ascorbylpalmitate and citric acid, natural tocopherols, L-(+)-ascorbylpalmitate, L-(+)-ascorbic acid and citric acid (for example Oxynex® KLIQUID), tocopherol extracts from natural sources, L-(+)-ascorbylpalmitate, L-(+)-ascorbic acid and citric acid (for example Oxynex® LLIQUID), DL-α-tocopherol, L-(+)-ascorbyl palmitate, citric acid andlecithin (for example Oxynex® LM) or butylhydroxytoluene (BHT),L-(+)-ascorbyl palmitate and citric acid (for example Oxynex® 2004).Antioxidants of this type are usually employed in such preparations withthe compounds according to the invention in percent by weight ratios inthe range from 1000:1 to 1:1000, preferably in percent by weight ratiosof 100:1 to 1:100.

Of the phenols, the polyphenols, such as flavonoids or bioflavonoids,which are principally known as plant dyes, frequently have anantioxidant potential. Quercetin (cyanidanol, cyanidenolon 1522,meletin, sophoretin, ericin, 3,3′,4′,5,7-pentahydroxyflavone) is anotherantioxidant agent suitable for compositions of the invention.

In another aspect, there is provided a kit comprising a composition ofthe invention and instructions for using said composition for sunlesstanning. In a particular embodiment the instructions are printed onpackaging containing said composition.

The invention will now be illustrated by the following non-limitingExamples.

EXAMPLES

All chemicals were purchased from Sigma Chemicals, St. Louis, Mo. Allcompounds were characterized by 1H NMR, 13C NMR, mass and melting pointanalysis. Nuclear Magnetic Resonance spectra were recorded on a VarianXL 600 MHz instrument. All 1H and ¹³C NMR experiments are reported inunits, parts per million (ppm), and were measured relative to residualDMSO in the deuterated solvent. All coupling constants were reported inHz. Melting points were determined on Mel-Temp II apparatus and areuncorrected. Mass analyses were performed on Agilent LC-TOF 1100 massspectrometer equipped with either an ESI or APCI source.

Example 1: Preparation of Compounds 3a, 3b, 3c and 3d

To a solution of 1,3-dibromopropane (2.202 g, 10.07 mmol) in 50 mL ofanhydrous DMF was added O,O′-bis(trimethylsilyl)-thymine (2) (6.256 g,23.17 mmol). The solution was heated to 170° C. and stirred overnight.The reaction was cooled to 0° C. and 10 mL of water was added to thereaction mass to precipitate the product. The precipitated mass wasstirred for 15 min at 0° C. The solids were filtered off, washed with100 mL of chloroform-methanol (1:1) and dried under vacuum to givecompound 3a (2.351 g, 81%) as an off white solid. ¹H NMR (600 MHz,DMSO-d⁶): δ 11.20 (s, 2H), 7.51 (s, 2H), 3.71 (t, 4H, J=7.04 Hz), 1.91(t, 4H, J=7.04 Hz), 1.73 (s, 6H); ¹³C NMR (150 MHz, DMSO-d⁶): δ 164.72,151.36, 141.68, 108.98, 45.27, 28.31, 12.37; Mass (ESI-MS): 293.154(M+H); m.p: 330-334° C.; Compounds 3b, 3c and were prepared followingthe procedure described for compound 3a. 3b: ¹H NMR (600 MHz, DMSO-d⁶):δ 11.18 (s, 2H), 7.50 (s, 2H), 3.62 (br, 4H), 1.73 (s, 6H), 1.53 (br,4H); ¹³C NMR (150 MHz, DMSO-d⁶): δ 164.71, 151.35, 141.86, 108.90,47.16, 25.84, 12.37; Mass (ESI-MS): 307.157 (M+H); m.p: 348-350° C.; 3c:¹H NMR (600 MHz, DMSO-d⁶): δ 11.15 (s, 2H), 7.47 (s, 2H), 3.57 (t, 4H,J=7.05 Hz), 1.71 (s, 6H), 1.55 (quintet, 4H, J=7.05 Hz), 1.19 (brquintet, 2H, J=7.05 Hz); ¹³C NMR (150 MHz, DMSO-d⁶): δ 164.70, 151.29,141.85, 108.82, 47.37, 28.48, 23.12; 12.36; Mass (ESI-MS): 321.174(M+H); m.p: 250-252° C.; 3d: ¹H NMR (600 MHz, DMSO-d⁶): δ 11.14 (s, 2H),7.48 (s, 2H), 3.56 (t, 4H, J=7.04 Hz), 1.71 (s, 6H), 1.52 (br quintet,4H, J=7.05 Hz), 1.22 (br quintet, 4H, J=7.04 Hz); ¹³C NMR (150 MHz,DMSO-d⁶): δ 164.71, 151.29, 141.82, 108.82, 47.42, 28.77, 25.87; 12.35;Mass (ESI-MS): 354.141 (M+H); m.p: 233-235° C.

Example 2: Preparation of Compound 8

To a solution of thymine (1) in THF was added pyridine and the reactionwas cooled to 0° C. Benzoyl chloride was added carefully at 0° C. andthe reaction was stirred overnight at room temperature. The reactionmass was evaporated to give the crude solid which was purified by SiO₂flash chromatography to give the N3-benzoyl thymine (4) as a whitesolid. ¹H NMR (600 MHz, CD₃OD): δ 7.94 (m, 2H), 7.71 (t, 1H, J=7.3 Hz),7.57 (m, 2H), 7.38 (s, 1H), 1.90 (s, 3H); Mass (ESI-MS): 231.22 (M+H);m.p: 178-180° C.

To a solution of N³-benzoyl thymine in THF was added PPh₃ and DIAD andthe reaction was cooled to at 0° C. Compound 5 in THF was added to thereaction mass drop-wise and the reaction was slowly brought to roomtemperature. Stirring was continued overnight. The organic solvents wereevaporated to give the dark brown residue which was purified by SiO₂flash chromatography to give the NBz-bisthymine compound 6. ¹H NMR (600MHz, DMSO-d⁶): δ 7.91 (m, 4H), 7.74 (t, 2H, J=7.3 Hz), 7.67 (s, 2H),7.56 (m, 4H), 3.74 (t, 4H, J=Hz), 2.79 (t, 4H, J=Hz), 1.79 (s, 6H), 1.43(s, 9H); ¹³C NMR (150 MHz, DMSO-d⁶): δ 170.36, 163.49, 163.25, 155.57,150.01, 149.86, 143.07, 135.82, 135.78, 131.85, 131.57, 130.96, 130.60,129.89, 129.64, 108.78, 108.11, 79.92, 47.12, 45.67, 44.34, 43.12,28.15, 12.37, 12.22; Mass (ESI-MS): 630.33 (M+H); m.p: 164-166° C.

Compound 6 was dissolved in aqueous ammonia and stirred overnight atroom temperature. The reaction was evaporated under vacuum to give theoff-white solid which was purified by SiO₂ flash chromatography to givethe intermediate 7. ¹H NMR (600 MHz, DMSO-d⁶): δ 7.93 (s, 1H), 5.56 (t,1H), 5.21 (s, 1H), 5.06 (m, 1H), 4.99 (m, 1H), 4.36 (m, 1H), 4.06 (m,1H), 3.84 (m, 2H), 3.58-3.51 (m, 2H), 2.86 (s, 3H), 2.71 (s, 3H), 1.51(s, 9H); ¹³C NMR (150 MHz, DMSO-d⁶): δ 162.75, 157.15, 154.08, 151.74,135.97, 117.46, 117.14, 86.76, 85.62, 74.13, 70.08, 61.83, 36.22, 31.23,25.56; Mass (ESI-MS): 422.43 (M+H); m.p: 254-256° C.

Compound 7 was dissolved in a solution of 6N HCl in dioxane and water(1:1) and stirred at 25° C. overnight. The solvents were evaporatedunder vacuum to give an oily residue which was obtained as white solid 8after repeated evaporations with toluene. ¹H NMR (600 MHz, DMSO-d⁶): δ11.23 (s, 2H); 8.01 (s, 1H), 5.74 (t, 1H), 5.47 (s, 1H), 5.68 (m, 1H),5.01 (m, 1H), 4.93 (m, 1H), 4.53 (m, 1H), 4.01 (m, 2H), 3.85-3.65 (m,2H), 2.95 (s, 3H), 2.85 (s, 3H); ¹³C NMR (150 MHz, DMSO-d⁶): δ 165.81,159.17, 155.80, 152.65, 136.01, 118.23, 117.94, 88.23, 86.75, 74.93,71.48, 62.05, 36.76, 31.94; Mass (ESI-MS): 322.23 (M+H); m.p: >320° C.

Example 3: Preparation of Compound 9

To a solution of thymine 1 (5.01 g, 39.76 mmol) in anhydrous DMSO (135mL) was added 1-bromopropane (1.601 g, 13.01 mmol) and anhydrouspotassium carbonate (5.50 g, 39.28 mmol) and the resulting suspensionwas stirred for 10-12 h at room temperature. The solids were filteredoff and the filtrate was evaporated under reduced pressure at 50° C.leaving a colorless semisolid which was suspended 500 mL water andextracted with chloroform (3×125 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered and evaporated to give the light yellow solidwhich was recrystallized using absolute ethanol to give whitecrystalline solid 9a (0.875 g, 40.13% based on 1-bromopraopane). ¹H NMR(600 MHz, DMSO-d⁶): δ 11.19 (s, 1H), 7.5 (s, 1H), 3.59 (t, 2H, J=7.04Hz), 1.72 (s, 3H), 1.59 (app. sext, 2H), 0.82 (t, 3H, J=7.63 Hz); ¹³CNMR (150 MHz, DMSO-d⁶): δ 164.72, 151.32, 141.93, 108.72, 49.09, 22.16,12.34, 11.09; Mass (ESI-MS): 169.191 (M+H); m.p: 133-135° C.

Compounds 9b and 9c were prepared in following the procedure describedfor compound 9a. 9b: ¹H NMR (600 MHz, DMSO-d⁶): δ 11.16 (s, 1H), 7.49(s, 1H), 3.56 (t, 2H, J=7.05 Hz), 5.56 (t, 1H), 1.71 (s, 3H), 1.50-1.51(m, 2H), 1.20-1.24 (m, 6H), 0.82 (t, 2H, J=7.04 Hz); ¹³C NMR (150 MHz,DMSO-d⁶): δ 164.70, 151.28, 141.86, 108.78, 47.54, 31.26, 28.83, 25.89,22.39, 14.27, 12.32; Mass (ESI-MS): 211.135 (M+H); m.p: 126-128° C.; 9c:¹H NMR (600 MHz, DMSO-d⁶): δ 11.14 (s, 1H), 7.49 (s, 1H), 3.57 (t, 2H,J=7.63 Hz), 5.56 (t, 1H), 1.73 (s, 3H), 1.51-1.53 (m, 2H), 1.22 (m, 6H),0.83 (t, 2H, J=7.04 Hz); ¹³C NMR (150 MHz, DMSO-d⁶): δ 164.70, 151.29,141.86, 108.78, 47.54, 31.62, 29.01, 28.86, 26.23, 22.49, 14.35, 12.33,Mass (ESI-MS): 354.141 (M+H); 239.210; m.p: 112-114° C.

Example 4: Preparation of Compound 10

A solution of 3a (0.087 g, mmol) was dissolved in deionized water (175mL, degassed) at 90° C., allowed to cool to room temperature in a 500 mLPyrex flask. A stream of nitrogen was bubbled throughout the cooling toroom temperature. The solution was irradiated at 300 nm in a RayonettRPR 208 reactor and the reaction was monitored for the absorption at 270nm with a 50:1 aliquot test solution every 1 h until reaction wascomplete (6 h). The irradiation was stopped and the round bottom flaskwas ca. taken out of the reactor. The pH was adjusted to 9 withaq.NaHCO₃. KMnO₄ (15 mg, 1.3 eq) was added and stirred at roomtemperature for 4-5 h. Saturated aq. NaSH (10 mL) precipitated MnO₂which was removed by filtration. The carbonates in the filtrates weredecomposed by careful addition of formic acid. Concentration of thesolution to 30 mL furnished the photodimer as a crude product which wasrecrystallized from water to give the white solid 10 (0.048 g, 55.17%).¹H NMR (600 MHz, DMSO-d⁶): δ 10.25 (s, 2H), 4.05 (d, 2H, J=12.91 Hz),3.89 (m, 2H), 2.71 (m, 2H), 1.47-1.85 (m, 2H), 1.35 (s, 3H); ¹³C NMR(150 MHz, DMSO-d⁶): δ 170.11, 151.29, 60.18, 46.99, 45.11, 23.96, 20.42;Mass (ESI-MS): 292.115 (M+H); m.p: >340° C.

Example 5: Preparation of Compound 11

Compounds 11 were prepared in following the procedure described forcompound 10 in Example 4. ¹H NMR (600 MHz, DMSO-d⁶): δ ¹H NMR (600 MHz,DMSO-d⁶): δ 10.23 (s, 2H), 5.45 (t, 1H), 5.47 (s, 1H), 5.68 (m, 1H),5.01 (m, 1H), 4.93 (m, 1H), 4.53 (m, 1H), 4.01 (m, 2H), 3.85-3.65 (m,2H), 2.95 (s, 3H), 2.85 (s, 3H); ¹³C NMR (150 MHz, DMSO-d⁶): δ 165.81,159.17, 155.80, 152.65, 136.01, 118.23, 117.94, 88.23, 86.75, 74.93,71.48, 62.05, 36.76, 31.94; Mass (ESI-MS): 322.31 (M+H); m.p: >330° C.

Example 6: Preparation of Compound 12

Sodium hydride (60% in mineral oil, 1.34 g, 54.33 mmol) was slowly addedto a solution of thymine (6.025 g, 47.87 mmol) in dry DMSO (25 mL) andthe mixture was stirred for 2 h at 50° C.Bis-chloromethyl-1,1,3,3-tetramethyldisiloxane (5.021 g, 21.73 mmol) wasadded and the mixture was heated for 3 days at 100° C. Reaction wasbrought to RT and 20 mL water was added. The reaction mass was extractedwith ethyl acetate (3×50 mL). The organic layer was washed with water,brine and dried over anhydrous Na₂SO₄. The organic layer was filteredand dried under vacuum to yield the crude compound as white syrup whichwas recrystallized using a mixture of ethanol and ethyl acetate (9:1)and stored at −20° C. The precipitated compound was filtered and washedwith 20 mL ethanol and dried under vacuum to give a white solid (6.35 g,32.5%). ¹H NMR (600 MHz, DMSO-d⁶): δ (ppm) 11.14 (s, 1H), 10.89 (s, 1H),7.30 (s, 1H), 3.09 (s, 4H), 1.64 (s, 7H), 0.00 (s, 12H); ¹³C NMR (150MHz, DMSO-d⁶): δ 164.93, 151.50, 137.73, 108.15, 45.14, 11.92, 0.00;Mass (APCI Neg.): 409.15 (M−H); m.p: 288-290° C.

Example 7: Preparation of Compound 13

Sodium hydride 60% in oil (0.43 g, 10.7 mmol) was added to a suspensionof 1,1′ trimethylenebisthymine (1.51 g, 5.1 mmol) in dimethyl sulfoxide(80 mL) and stirred overnight at 60-65° C. 1, 3-Diiodopropane (1.63 g,4.8 mmol) was added to the reaction mixture and stirred for 3 days at80° C. to give a clear solution. The solvent was evaporated; theresidual solid was washed with potassium carbonate aqueous solution (30mL), methanol (20 mL), and diethyl ether (20 mL). The product in waspurified by silica gel column using ethyl acetate/methanol as eluents togive the cyclic compound, II as a white solid (0.204 g, 12%). ¹H NMR(600 MHz, CDCl₃, ppm): 7.05 (s, 2H, C6-H), 4.07 (t, 3H, N3-CH2), 3.75(t, 4H, N1-CH2), 2.15 (t, 2H, N3-C—CH2), 1.98 (t, 2H, N1-C—CH2), 1.89(s, 6H, C5-CH3); ¹³C NMR (150 MHz, CDCl₃): 164.11, 152.53, 141.21,108.15, 51.20, 45.73, 28.20, 26.35, 10.35; Mass (APCI-Neg): 331.13 (M−H)

Example 8: Preparation of Compounds 24a, 24b, 24c, 24d, 24e, and 24f

To a solution of Bis-(chloroethyl)amine, 22 (1.393 g, 9.816 mmol) inbenzene (20 mL) was added butyryl chloride (0.523 g, 4.908 mmol)dissolved in 10 mL benzene at 0° C. and stirred for 15 min. The reactionmass was refluxed for 1 h, cooled to RT and the precipitate was filteredoff. The filtrates were evaporated to give the corresponding amide 23(0.752 g, 72.3%) as a colorless oil. ¹H NMR (600 MHz, DMSO-d⁶): δ 3.75(t, 4H), 3.51 (t, 4H), 2.71 (t, 2H), 1.45 (m, 2H), 0.76 (t, 3H); Mass(ESI-MS): 212.143 (M+H).

Compound 23 (0.251 g, 1.189 mmol) was dissolved in anhydrous1,2-dcholoroethane (30 mL) at RT. O,O′-Bis(trimethylsilyl)-thymine(0.738 g, 2.733 mmol) was added in one portion followed by the additionof catalytic I₂ (14 mG, 0.05 eqv) and refluxed for 24 h. The reactionmass was evaporated to give the crude solid which was purified by SiO₂flash chromatography to give the compound 24a (0.301 g, 70.82%) as anoff white solid. ¹H NMR (600 MHz, DMSO-d⁶): δ 11.30 (s, 1H); 11.10 (s,1H); 7.49 (s, 1H); 7.31 (s, 1H); 3.76 (t, 4H), 3.47 (t, 4H), 2.09 (t,2H), 1.72 (s, 3H); 1.68 (s, 3H); 1.36 (t, 2H), 0.75 (t, 3H); ¹³C NMR(150 MHz, DMSO-d⁶): δ 173.71, 164.41, 163.55, 152.23, 151.35, 141.74,141.13, 109.23, 108.95, 57.74, 57.63, 47.63, 47.55, 35.84, 19.37, 13.55,12.33, 12.21; Mass (ESI-MS): 392.19 (M+H); m.p: 298-300° C.

Compounds 24b, 24c, 24d, 24e and 24f were prepared following theprocedure described for compound 24a. 24b: ¹H NMR (600 MHz, DMSO-d⁶): δ11.52 (s, 1H); 11.31 (s, 1H); 7.55 (s, 1H); 7.41 (s, 1H); 3.72 (t, 4H),3.43 (t, 4H), 2.11 (t, 2H), 1.75 (s, 3H); 1.65 (s, 3H); 1.53 (t, 2H),1.33 (m, 2H); 1.29-1.25 (m, 22H); 0.95 (t, 3H); ¹³C NMR (150 MHz,DMSO-d⁶): δ 173.15, 163.23, 163.10, 151.54, 151.43, 140.15, 139.85,110.23, 110.20, 58.32, 58.30, 47.53, 47.50, 47.41, 35.33, 32.33, 30.68,29.77, 29.75, 29.73, 29.72, 29.70, 29.68, 29.65, 28.98, 28.03, 23.15,15.15, 12.85, 12.73; Mass (ESI-MS): 560.41 (M+H); m.p: 285-288° C. 24c:¹H NMR (600 MHz, DMSO-d⁶): δ 11.68 (s, 1H); 11.53 (s, 1H); 7.58 (s, 1H);7.49 (s, 1H); 3.78 (t, 4H), 3.51 (t, 4H), 2.35 (t, 2H), 1.85 (s, 3H);1.78 (s, 3H); 1.63 (t, 2H), 1.46 (m, 2H); 1.35-1.21 (m, 28H); 0.98 (t,3H); ¹³C NMR (150 MHz, DMSO-d⁶): δ 173.31, 163.95, 163.23, 151.73,151.81, 141.16, 140.95, 110.55, 110.34, 58.54, 58.50, 47.64, 47.61,47.58, 35.43, 32.41, 30.72, 29.82, 29.75, 29.63, 29.71, 29.67, 29.65,29.64, 29.61, 29.58, 28.88, 28.53, 23.45, 15.24, 12.21, 12.13; Mass(ESI-MS): 588.51 (M+H); m.p: 310-312° C. 24d: ¹H NMR (600 MHz, DMSO-d⁶):δ 11.57 (s, 1H), 11.48 (s, 1H), 8.33-7.68 (m, 5H), 7.54 (s, 1H), 7.45(s, 1H), 3.81 (t, 4H), 3.76 (t, 4H), 1.71 (s, 3H), 1.68 (s, 3H); ¹³C NMR(150 MHz, DMSO-d⁶): δ 170.71, 151.20, 150.11, 140.82, 139.95, 136.35,129.36, 128.85, 128.73, 127.63, 109.83, 108.95, 58.54, 58.35, 48.42,48.38, 28.77, 25.87; 12.35, 12.25; Mass (ESI-MS): 426.14 (M+H); m.p:320-322° C. 24e: ¹H NMR (600 MHz, DMSO-d⁶): δ 11.63 (s, 1H), 11.53 (s,1H), 8.43-7.87 (m, 5H), 7.64 (s, 1H), 7.59 (s, 1H), 7.37 (s, 1H), 7.28(s, 1H) 3.73 (t, 4H), 3.64 (t, 4H), 1.81 (s, 3H), 1.76 (s, 3H); ¹³C NMR(150 MHz, DMSO-d⁶): δ 171.65, 152.21, 151.31, 142.24, 141.84, 140.55,137.31, 130.26, 129.15, 129.13, 128.33, 120.33, 110.33, 110.51, 58.76,58.55, 49.32, 49.71, 28.34, 26.67; 12.51, 12.45; Mass (ESI-MS): 452.17(M+H); m.p: 315-317° C. 24f: ¹H NMR (600 MHz, DMSO-d⁶): δ 11.45 (s, 1H),11.37 (s, 1H), 7.78-6.35 (m, 5H), 7.24 (s, 1H), 7.01 (s, 1H), 6.77 (s,1H), 3.41 (t, 4H), 3.26 (t, 4H), 1.81 (s, 3H), 1.78 (s, 3H); Mass(ESI-MS): 482.45 (M+H); m.p: 298-300° C.

Example 9: Preparation of Compound 28

To a solution of acid 25 (1.752 g, 10.068 mmol) in anhydrous DCM (50 mL)was added 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide. HCl (2.922 g,15.303 mmol) and N-hydroxybenzotriazole (2.038 g, 15.103 mmol) at 0° C.and stirred for 15 min. Bis-(chloroethyl) amine, 22 (1.511 g, 10.709mmol) in DCM (10 mL) was added and the reaction mass was stirredovernight at RT. The reaction mass diluted with 50 mL of DCM and washedwith aq. NaHO₃ solution (20 ml) and brine (20 mL). The organic layer wasdried over anhydrous Na₂SO₄ and concentrated under vacuum to give thecrude product which was purified by SiO₂ flash chromatography to givethe compound 26 (2.651 g, 75%) as a colorless oil. ¹H NMR (600 MHz,DMSO-d⁶): δ 3.92 (t, 1H), 3.82-3.75 (m, 4H), 3.68 (m, 4H), 2.98-2.94(dd, 2H), 1.55 (s, 3H), 1.59 (s, 3H); Mass (ESI-MS): 298.13 (M+H).

Compound 26 (1.253 g, 4.218 mmol) was dissolved in anhydrous1,2-dcholoroethane (30 mL) at RT. O,O′-Bis(trimethylsilyl)-thymine(2.505 g, 9.281 mmol) was added in one portion followed by the additionof catalytic I₂ (20 mG, 0.05 eqv) and refluxed for 24 h. The reactionmass was evaporated to give the crude solid which was purified by SiO₂flash chromatography to give the compound 27 (1.153 g, 56.79%) as an offwhite solid. ¹H NMR (600 MHz, DMSO-d⁶): δ 11.29 (s, 1H), 11.13 (s, 1H),7.48 (s, 1H), 7.29 (s, 1H), 4.71 (t, 1H), 3.74-3.71 (m, 4H), 3.60-3.52(m, 4H), 3.21-3.32 (m, 2H) 1.72 (s, 3H), 1.70 (s, 3H), 1.44 (s, 6H);Mass (ESI-MS): 478.67 (M+H); m.p: 285-287° C.

Compound 27 (0.851 g) was dissolved in 12N HCl in water and stirredovernight at RT. The reaction mass was concentrated under vacuum and theresidue was freeze dried to obtain the compound 28 as white solid (0.725g, 96%). ¹H NMR (600 MHz, DMSO-d⁶): δ 12.01 (br s, 1H), 11.36 (s, 1H),11.23 (s, 1H), 7.57 (s, 1H), 7.37 (s, 1H), 4.34 (t, 1H), 3.82-3.75 (m,4H), 3.71-3.58 (m, 4H), 3.31-3.28 (m, 2H), 2.83 (d, 1H), 1.79 (s, 3H),1.80 (s, 3H), 1.78 (s, 6H); ¹³C NMR (150 MHz, DMSO-d⁶): δ 176.15,171.87, 153.14, 152.34, 142.65, 142.11, 140.96, 137.84, 131.25, 129.62,129.33, 128.72, 120.84, 109.31, 109.85, 71.21, 58.54, 49.75, 36.23,28.34, 26.54; 12.35, 12.29; Mass (ESI-MS): 438.77 (M+H); m.p: 321-323°C.

Example 10: Preparation of Compound 32

To a solution of acid 29 (1.250 g, 4.045 mmol) in anhydrous DCM (50 mL)was added 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide. HCl (0.819 g,6.067 mmol) and N-hydroxybenzotriazole (1.158 g, 6.067 mmol) at 0° C.and stirred for 15 min. Bis-(chloroethyl)amine, 22 (0.684 g, 4.854 mmol)in DCM (10 mL) was added and the reaction mass was stirred overnight atRT. The reaction mass diluted with 50 mL of DCM and washed with aq.NaHO₃ solution (20 ml) and brine (20 mL). The organic layer was driedover anhydrous Na₂SO₄ and concentrated under vacuum to give the crudeproduct which was purified by SiO₂ flash chromatography to give thecompound 30 (1.035 g, 59.24%) as a colorless oil. ¹H NMR (600 MHz,DMSO-d⁶): δ 4.81 (m, 1H), 3.84-3.78 (m, 4H), 3.70-3.64 (m, 4H),3.01-2.86 (dd, 2H), 1.43 (s, 9H), 1.34 (s, 9H); Mass (ESI-MS): 433.45(M+H).

Compound 30 (0.752 g, 1.74 mmol) was dissolved in anhydrous1,2-dcholoroethane (50 mL) at RT. O,O′-Bis(trimethylsilyl)-thymine(1.445 g, 5.353 mmol) was added in one portion followed by the additionof catalytic I₂ (20 mG) and refluxed for 24 h. The reaction mass wasevaporated to give the crude solid which was purified by SiO₂ flashchromatography to give the compound 11 (0.575 g, 55.82%) as an off whitesolid. ¹H NMR (600 MHz, DMSO-d⁶): δ 11.63 (s, 1H), 11.45 (s, 1H), 7.54(s, 1H), 7.50 (s, 1H), 4.93 (m, 1H), 4.01-3.84 (m, 4H), 3.91-3.72 (m,4H), 3.76-2.92 (dd, 2H), 1.75 (s, 6H), 1.51 (s, 9H), 1.45 (s, 9H); Mass(ESI-MS): 613.51 (M+H); m.p: 275-280° C.

Compound 31 (0.425 g, 0.857 mmol) was dissolved in THF-H₂O (1:1) andtri-butyl phosphine (0.173 g, 1.027 mmol) was added and the reactionmass was stirred at RT for 24 h.

The solvents were evaporated to give the crude solid which was purifiedby SiO₂ flash chromatography to give the compound 32 (0.245 g, 67.5%) aswhite solid. ¹H NMR (600 MHz, DMSO-d⁶): δ 11.74 (s, 1H), 11.65 (s, 1H),7.36 (s, 1H), 7.31 (s, 1H), 5.01 (m, 1H), 4.17-4.01 (m, 4H), 3.98-3.81(m, 4H), 3.76-3.52 (dd, 2H), 1.73 (s, 6H), 1.35 (s, 9H); ¹³C NMR (150MHz, DMSO-d⁶): δ 170.11, 163.65, 163.52, 155.81, 151.43, 151.38, 140.61,110.32, 80.21, 58.67, 57.43, 47.81, 28.21, 28.18, 28.17 27.51, 12.25,12.28; Mass (ESI-MS): 525.13 (M+H); m.p: 300-305° C.

Example 11: Preparation of Compounds 115 and 116

To a solution of O,O′-Bis(trimethylsilyl)-thymine (0.401 g, 1.482 mmol)in anhydrous DMF was added the dibromoester, 113 (0.255 g, 0.988 mmol)at RT and the reaction was heated to 75-80° C. The reaction mass wasevaporated to give an oily residue which was purified by SiO₂ flashchromatography to give the compound 114 (0.143 g, 64.7%) as an off whitesolid. ¹H NMR (600 MHz, DMSO-d⁶): δ 11.09 (s, 1H), 7.23 (s, 1H), 6.26(s, 1H), 5.52 (s, 1H), 4.01 (s, 2H), 3.43 (s, 3H), 1.85 (s, 3H); Mass(ESI-MS): 224.36 (M+).

To a solution of compound 114 (0.125 g, 0.558 mmol) in acetonitrile (30mL) was added the O,O′-Bis(trimethylsilyl)-thymine (0.181 g, 0.669 mmol)at RT and the reaction was stirred at RT. The reaction mass wasevaporated to give the crude solid which was purified by SiO₂ flashchromatography to give the compound 115 (0.139 g, 71.28%) as an offwhite solid. ¹H NMR (600 MHz, DMSO-d⁶): δ 11.25 (s, 2H), 7.46 (s, 2H),3.83 (d, 4H), 3.54 (s, 3H), 3.43 (m, 1H), 1.71 (s, 6H); ¹³C NMR (150MHz, DMSO-d⁶): δ 174.12, 164.51, 151.35, 139.24, 53.11, 50.23, 40.34,15.21, 15.18; Mass (ESI-MS): 351.75 (M+H).

To a solution of compound 115 (0.113 g, 0.322 mmol) in water (10 mL) wasadded 1N NaOH (10 mL) at 0° C. and stirred carefully for 2-3 h. The pHof the reaction was adjusted to acidic (pH-2) and the precipitatedreaction mass was filtered, washed with dioxane-MeOH (1:1, 20 mL) anddried under vacuum to give the compound 116 (0.072 g, 66.71%) as a whitesolid. ¹H NMR (600 MHz, DMSO-d⁶): δ 12.81 (s. 1H), 11.24 (s, 2H), 7.44(s, 2H), 3.81 (d, 4H), 3.15 (m, 1H), 1.70 (s, 6H); ¹³C NMR (150 MHz,DMSO-d⁶): δ 179.25, 164.87, 152.33, 140.27, 51.47, 42.33, 16.22, 16.20;Mass (ESI-MS): 335.13 (M−H).

Example 12: Preparation of Salts 117 and 118

To a solution of the acid 116 (0.105 g, 0.312 mmol) in water (20 mL) wasslowly added N,N-dimethylaminoethanol (DMAE) (0.027 g, 0.312 mmol)) atRT. The contents were stirred for 1-2 h at RT. The solvent waslyophilized to give an amorphous solid which was washed with diethylether (25 mL) and dried under vacuum to give the DMAE salt of the acid117, as an off white powder. (0.125 g, 94%). ¹H NMR (600 MHz, DMSO-d⁶):δ 10.76 (s, 2H), 7.16 (s, 2H), 3.71 (d, 4H), 3.42 (d, 2H), 3.01 (m, 1H),2.71 (d, 2H), 2.44 (s, 6H), 1.63 (s, 6H); Mass (ESI-MS): 335.46 (M−H)

To a solution of the acid 116 (0.125 g, 0.372 mmol)) in water (20 mL)was slowly added glucosamine (0.066 g, 0.372 mmol) at RT. The contentswere stirred for 1-2 h at RT. The solvent was lyophilized to give anamorphous solid and washed with diethyl ether (30 mL). The solids weredried under vacuum to give the glucosamine salt of the acid 118, as awhite powder (0.173 g, 90.57%). ¹H NMR (600 MHz, DMSO-d⁶): 11.12 (s,2H), 7.21 (s, 2H), 5.65 (d, 1H), 4.12-3.81 (m, 1H), 4.01-2.91 (m, 1H),3.73 (d, 4H), 3.66 (m, 1H), 3.45 (m, 1H), 1.71 (s, 6H); Mass (ESI-MS):335.87 (M−H).

Example 13: Preparation of Compound 121

To a solution of O,O′-Bis(trimethylsilyl)-thymine (1.186 g, 4.392 mmol)was added 3-chloro-(2-chloromethyl)prop-1-ene (0.252 g, 1.640 mmol), NaI(20 mG, 0.157 mmol) and potassium carbonate (0.559 g, 3.992 mmol) inanhydrous DMF (50 mL). The mixture was heated to 80° C. and stirredovernight. DMF was evaporated and the residue was purified by SiO₂ flashchromatography to give the compound 119 as a white solid (0.345 g,56.3%). ¹H NMR (600 MHz, DMSO-d⁶): 11.23 (s, 2H), 7.01 (s, 2H), 5.45 (s,1H), 5.21 (s, 1H), 5.65 (d, 1H), 3.81 (s, 4H); 1.75 (s, 6H); Mass(ESI-MS): 304.71 (M+).

Compound 119 (0.301 g, 0.99 mmol) was dissolved in a mixture of THF-H₂O(1:0.5 ratio; 30 mL). Sodium-periodate (1.059 g, 4.948 mmol) was addedin portion and stirred for 10 min at RT. Potassium osmate(VI) dihydrate(0.036 g, 0.099 mmol) was added to the reaction mass and stirredovernight at RT. The solvents were evaporated and methanol (10 mL) wasadded to dissolve the product and filtered. The filtrate were evaporatedand the residue was purified by SiO₂ flash chromatography to give thecompound 120 as a white solid (0.125 g, 41.31%). ¹H NMR (600 MHz,DMSO-d⁶): 11.12 (s, 2H), 6.31 (s, 2H), 4.13 (s, 4H), 1.81 (s, 6H); ¹³CNMR (150 MHz, DMSO-d⁶): δ 198.12, 163.34, 151.17, 140.57, 110.34, 55.73,15.23, 15.22; Mass (ESI-MS): 304.63 (M+); m.p: 320-331° C.

The compound 120 (0.158 g, 0.516 mmol) was suspended in H₂O (20 mL) andcooled to 0° C. Sodiumborohydride (0.191 g, 5.613 mmol) was carefullyadded to the reaction mixture in two portions. The reaction was stirredfor 2 h at 0° C. and slowly brought to RT. Methanol (10 mL) wascarefully introduced followed by the addition of H₂O (25 mL) toprecipitate the solids. The compound was recrystallized using a mixtureof water and ethanol (1:1) to give the compound 121 as a white solid(0.105 g, 66.03%). ¹H NMR (600 MHz, DMSO-d⁶): 11.01 (s, 2H), 6.45 (s,2H), 4.66-3.33 (m, 6H), 2.11 (s, 6H); ¹³C NMR (150 MHz, DMSO-d⁶): δ165.37, 150.43, 142.51, 111.57, 65.77, 1.23, 15.31, 15.28; Mass(ESI-MS): 308.71 (M+); m.p: 319-322° C.

Example 14: Preparation of Compound 122

A solution of 115 (0.052 g, 0.148 mmol) was dissolved in deionized water(100 mL, degassed) at 90° C., allowed to cool to room temperature in a500 mL Pyrex flask. A stream of nitrogen was bubbled throughout thecooling to room temperature. The solution was irradiated at 300 nm in aRayonet RPR 208 reactor and the reaction was monitored for theabsorption at 270 nm with a 50:1 aliquot test solution every 1 h untilreaction was complete (6 h). The irradiation was stopped and the roundbottom flask was ca. taken out of the reactor. The pH was adjusted to 9with aq.NaHCO₃. KMnO₄ (10 mg, 1.3 eqv) was added and stirred at roomtemperature for 4-5 h. Saturated aq. NaSH (10 mL) precipitated MnO₂which was removed by filtration. The carbonates in the filtrates weredecomposed by careful addition of formic acid. Concentration of thesolution to 30 mL furnished the photodimer as a crude product which wasrecrystallized from water to give the white solid 122 (0.025 g, 48.07%).¹H NMR (600 MHz, DMSO-d⁶): δ 10.35 (s, 2H), 4.01 (d, 2H), 3.76 (d, 4H),3.54 (s, 3H), 3.21 (m, 1H), 1.35 (s, 6H); ¹³C NMR (150 MHz, DMSO-d⁶): δ173.21, 161.15, 151.35, 57.13, 40.45, 15.33, 15.28; Mass (ESI-MS):351.25 (M+H).

Example 15: Preparation of Salts 123 and 124

A solution of DMAE salt of the acid, 117 (0.095 g, 0.223 mmol) wasdissolved in deionized water (100 mL, degassed) in a 500 mL Pyrex flask.A stream of nitrogen was bubbled throughout the cooling to roomtemperature. The solution was irradiated at 300 nm in a Rayonet RPR 208reactor and the reaction was monitored for the absorption at 270 nm witha 50:1 aliquot test solution every 1 h until reaction was complete (6h). The irradiation was stopped and the round bottom flask was ca. takenout of the reactor. The pH was adjusted to 9 with aq.NaHCO₃. KMnO₄ (10mg, 1.3 eqv) was added and stirred at room temperature for 4-5 h.Saturated aq. NaSH (10 mL) precipitated MnO₂ which was removed byfiltration. The carbonates in the filtrates were decomposed by carefuladdition of formic acid. Concentration of the solution to 30 mLfurnished the photodimer as a crude product which was recrystallizedfrom water to give the white solid 123 (0.054 g, 56.84%). ¹H NMR (600MHz, DMSO-d⁶): δ 10.22 (s, 2H), 4.22 (d, 2H), 3.97-3.86 (d, 4H), 3.76(d, 4H), 3.54 (s, 3H), 3.21 (m, 1H), 3.11 (m, 1H), 2.61 (d, 2H), 2.47(s, 6H), 1.31 (s, 6H); ¹³C NMR (150 MHz, DMSO-d⁶): δ 179.31, 161.60,153.54, 59.13, 65.12, 59.10, 58.64, 52.34, 47.25, 46.67, 41.45, 14.31,14.27; Mass (ESI-MS): 335.65 (M+H).

Compound 124 was prepared from the glucosamine salt of the acid (118) infollowing the procedure described for compound 123. ¹H NMR (600 MHz,DMSO-d⁶): δ 11.23 (s, 2H), 5.54 (d, 1H), 4.22-3.95 (m, 1H), 4.11-3.01(m, 1H), 3.43 (d, 4H), 3.76 (m, 1H), 3.55 (m, 1H), 1.71 (s, 6H); ¹³C NMR(150 MHz, DMSO-d⁶): δ 178.35, 161.75, 152.34, 100.12, 59.33, 71.23,74.24, 66.21, 65.23, 63.15, 59.56, 58.34, 57.43, 52.71, 47.35, 46.61,41.51, 14.23, 14.19; Mass (ESI-MS): 335.55 (M+H).

Example 16

The following illustrate representative compositions of the inventioncontaining a compound of formula I (‘Compound X’).

(i) Tablet 1 mg/tablet Compound X = 100.0 Lactose 77.5 Povidone 15.0Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesiumstearate 3.0 300.0 (ii) Tablet 2 mg/tablet Compound X = 20.0Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate15.0 Magnesium stearate 5.0 500.0 (iii) Capsule mg/capsule Compound X =10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch120.0 Magnesium stearate 3.0 600.0 (iv) Injection 1 (1 mg/ml) mg/mlCompound X = (free acid form) 1.0 Dibasic sodium phosphate 12.0Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0N Sodium hydroxidesolution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1mL (v) Injection 2 (10 mg/ml) mg/ml Compound X = (free acid form) 10.0Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethyleneglycol 400 200.0 1.0N Sodium hydroxide solution q.s. (pH adjustment to7.0-7.5) Water for injection q.s. ad 1 mL (vi) Aerosol mg/can Compound X= 20.0 Oleic acid 10.0 Trichloromonofluoromethane 5,000.0Dichlorodifluoromethane 10,000.0 Dichlorotetrafluoroethane 5,000.0

Example 17

The following illustrates a representative dermatological compositionsof the invention containing a compound as described in Formula I orFormula II (‘Compound X’).

Cream: 2-12% Active ingredients (Compound X) and 88-98% Inactiveingredients Inactive Ingredients % (w/w) Water 65 Hexadecan-1-ol(C₁₆H₃₄O, Cetyl alcohol) 3.0 Octadecan-1-ol (C₁₈H₃₈O, Stearyl alcohol)8.5 Isopropyl myristate (C₁₇H₃₄O₂) 1.0 Glycerine 0.3 Propylene glycol20.0 Polysorbate 20 (TWEEN 20) 2.0 Isopropyl palmitate 0.2 Total forinactive ingredients 100.00The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art.

Example 18: Pigment Changes with Topical Application of Compounds 10,117 and 123

Compounds 10, 117 and 123 in a solution of 75% PG/25% DMSO at 300 μM and600 μM were provided in light tight containers and stored at 4 degreesC. Solutions were brought to room temp and vortexed prior to each use.Female Guinea pigs were shaved with electric clippers and the remainingstubble removed with Nair. The dorsal area of each guinea pig wasdivided into 2-3 sections. Treatment with compounds/vehicle beganimmediately after Nair application. 25 μL of each solution was appliedto the assigned treatment site twice daily for 5 days. Hair removal,monitoring and photography continued once weekly for 30 days. Photoswere taken with a Nikon D80 Digital SLR camera and Miravex AnteraMelanin sensing camera.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specificembodiments and techniques. However, it should be understood that manyvariations and modifications may be made while remaining within thespirit and scope of the invention.

What is claimed is:
 1. A method of tanning mammalian skin comprisingadministering to mammalian skin in need thereof, an effective amount ofa sunless tanning composition comprising a compound of formula I:

wherein: each R¹ is independently H, (C₁-C₆)alkyl, (C₃-C₇)carbocycle orR_(a)C(═O)—, and the two R⁴ groups together form a —(C₃-C₈)alkyl- group,a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl- group or a—(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; or each R⁴ is independently H,(C₁-C₆)alkyl, (C₃-C₇)carbocycle or R_(a)C(═O)—, and the two R¹ groupstogether form a —(C₃-C₈)alkyl- group, a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl-group or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; or the two R⁴ groupstogether form a —(C₃-C₈)alkyl- group, a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkylgroup or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group and the two R¹ groupstogether form a —(C₃-C₈)alkyl- group, a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl-group or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; the dashed bondslabeled “a” are absent and the dashed bonds labeled “b” are doublebonds; or all the dashed bonds are single bonds; R² is H, (C₁-C₆)alkylor aryl, wherein aryl is optionally substituted with one or more Z¹groups; R³ is H, (C₁-C₆)alkyl or aryl, wherein aryl is optionallysubstituted with one or more Z¹ groups; Y is O, S, NH, NR_(c), P, P(═O)or POH; Y′ is Si(R_(b))₂ or —Si(R_(b))₂—O—Si(R_(b))₂—; each R_(a) isindependently (C₁-C₆)alkyl, (C₃-C₇)carbocycle or aryl, wherein aryl isoptionally substituted with one or more Z¹ groups; each R_(b) isindependently (C₁-C₆)alkyl, (C₃-C₇)carbocycle or aryl, wherein aryl isoptionally substituted with one or more Z¹ groups; each R_(c) isindependently R_(g) or a C₁-C₁₈ saturated or unsaturated carbon chainthat is optionally substituted with one or more groups independentlyselected from oxo (═O), hydroxy, mercapto, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, NR_(d)R_(e), carboxy, andaryl, wherein any aryl of R_(c) is optionally substituted with one ormore R_(f); each R_(d) and R_(e) is independently selected from H,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, phenyl, benzyl, and R_(g); each R_(f) isindependently selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, —C(═O)-phenyl, and—C(═O)CH₂C(═O)-phenyl, wherein any phenyl is optionally substituted withone or more groups independently selected from (C₁-C₆)alkyl, —SO₃H, and(C₁-C₆)alkoxy; each R_(g) is

each Z¹ is independently selected from (C₁-C₆)alkyl, halogen, —CN,—OR_(n1), —NR_(q1)R_(r1), —NR_(n1)COR_(p1), —NR_(n1)CO₂R_(p1), NO₂,—C(O)R_(n1), —C(O)OR_(n1) and —C(O)NR_(q1)R_(r1), wherein any(C₁-C₆)alkyl of Z¹ is optionally substituted with one or more (e.g. 1,2, 3, 4, 5 or 6) halogen; each R_(n1) is independently selected from Hand (C₁-C₆)alkyl, wherein any (C₁-C₆)alkyl of R_(n1) is optionallysubstituted with one or more (e.g. 1, 2, 3, 4, 5 or 6) halogen; eachR_(p1) is independently (C₁-C₆)alkyl; and R_(q1) and R_(r1) are eachindependently selected from H and (C₁-C₆)alkyl or R_(q1) and R_(r1)together with the nitrogen to which they are attached form a piperidine,pyrrolidine, morpholine, azetidine, thiomorpholine, piperazine or4-methylpiperazine; or a salt thereof.
 2. The method of claim 1 whereinthe wherein the sunless tanning composition comprises a compound offormula I selected from:

or a salt thereof.
 3. A method of providing an artificial tan tomammalian skin comprising administering to mammalian skin in needthereof, an effective amount of a sunless tanning composition comprisinga compound of formula I:

wherein: each R¹ is independently H, (C₁-C₆)alkyl, (C₃-C₇)carbocycle orR_(a)C(═O)—, and the two R⁴ groups together form a —(C₃-C₅)alkyl- group,a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl- group or a—(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; or each R⁴ is independently H,(C₁-C₆)alkyl, (C₃-C₇)carbocycle or R_(a)C(═O)—, and the two R¹ groupstogether form a —(C₃-C₅)alkyl- group, a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl-group or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; or the two R⁴ groupstogether form a —(C₃-C₅)alkyl- group, a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkylgroup or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group and the two R¹ groupstogether form a —(C₃-C₈)alkyl- group, a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl-group or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; the dashed bondslabeled “a” are absent and the dashed bonds labeled “b” are doublebonds; or all the dashed bonds are single bonds; R² is H, (C₁-C₆)alkylor aryl, wherein aryl is optionally substituted with one or more Z¹groups; R³ is H, (C₁-C₆)alkyl or aryl, wherein aryl is optionallysubstituted with one or more Z¹ groups; Y is O, S, NH, NR_(c), P, P(═O)or POH; Y′ is Si(R_(b))₂ or —Si(R_(b))₂—O—Si(R_(b))₂—; each R_(a) isindependently (C₁-C₆)alkyl, (C₃-C₇)carbocycle or aryl, wherein aryl isoptionally substituted with one or more Z¹ groups; each R_(b) isindependently (C₁-C₆)alkyl, (C₃-C₇)carbocycle or aryl, wherein aryl isoptionally substituted with one or more Z¹ groups; each R_(c) isindependently R_(g) or a C₁-C₁₈ saturated or unsaturated carbon chainthat is optionally substituted with one or more groups independentlyselected from oxo (═O), hydroxy, mercapto, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, NR_(d)R_(e), carboxy, andaryl, wherein any aryl of R_(c) is optionally substituted with one ormore R_(f); each R_(d) and R_(e) is independently selected from H,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, phenyl, benzyl, and R; each R_(f) isindependently selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, —C(═O)-phenyl, and—C(═O)CH₂C(═O)-phenyl, wherein any phenyl is optionally substituted withone or more groups independently selected from (C₁-C₆)alkyl, —SO₃H, and(C₁-C₆)alkoxy; each R_(g) is

each Z¹ is independently selected from (C₁-C₆)alkyl, halogen, —CN,—OR_(n1), —NR_(q1)R_(r1), —NR_(n1)COR_(p1), —NR_(n1)CO₂R_(p1), NO₂,—C(O)R_(n1), —C(O)OR_(n1) and —C(O)NR_(q1)R_(r1), wherein any(C₁-C₆)alkyl of Z¹ is optionally substituted with one or more (e.g. 1,2, 3, 4, 5 or 6) halogen; each R_(n1) is independently selected from Hand (C₁-C₆)alkyl, wherein any (C₁-C₆)alkyl of R_(n1) is optionallysubstituted with one or more (e.g. 1, 2, 3, 4, 5 or 6) halogen; eachR_(p1) is independently (C₁-C₆)alkyl; and R_(q1) and R_(r1) are eachindependently selected from H and (C₁-C₆)alkyl or R_(q1) and R_(r1)together with the nitrogen to which they are attached form a piperidine,pyrrolidine, morpholine, azetidine, thiomorpholine, piperazine or4-methylpiperazine; or a salt thereof.
 4. The method of claim 3 whereinthe wherein the sunless tanning composition comprises a compound offormula I selected from:

or a salt thereof.
 5. A method of coloring mammalian skin, comprisingadministering to mammalian skin in need thereof, an effective amount ofa sunless tanning composition comprising a compound of formula I:

wherein: each R¹ is independently H, (C₁-C₆)alkyl, (C₃-C₇)carbocycle orR_(a)C(═O)—, and the two R⁴ groups together form a —(C₃-C₅)alkyl- group,a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl- group or a—(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; or each R⁴ is independently H,(C₁-C₆)alkyl, (C₃-C₇)carbocycle or R_(a)C(═O)—, and the two R¹ groupstogether form a —(C₃-C₅)alkyl- group, a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl-group or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; or the two R⁴ groupstogether form a —(C₃-C₅)alkyl- group, a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkylgroup or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group and the two R¹ groupstogether form a —(C₃-C₈)alkyl- group, a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl-group or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; the dashed bondslabeled “a” are absent and the dashed bonds labeled “b” are doublebonds; or all the dashed bonds are single bonds; R² is H, (C₁-C₆)alkylor aryl, wherein aryl is optionally substituted with one or more Z¹groups; R³ is H, (C₁-C₆)alkyl or aryl, wherein aryl is optionallysubstituted with one or more Z¹ groups; Y is O, S, NH, NR_(c), P, P(═O)or POH; Y′ is Si(R_(b))₂ or —Si(R_(b))₂—O—Si(R_(b))₂—; each R_(a) isindependently (C₁-C₆)alkyl, (C₃-C₇)carbocycle or aryl, wherein aryl isoptionally substituted with one or more Z¹ groups; each R_(b) isindependently (C₁-C₆)alkyl, (C₃-C₇)carbocycle or aryl, wherein aryl isoptionally substituted with one or more Z¹ groups; each R_(c) isindependently R_(g) or a C₁-C₁₈ saturated or unsaturated carbon chainthat is optionally substituted with one or more groups independentlyselected from oxo (═O), hydroxy, mercapto, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, NR_(d)R_(e), carboxy, andaryl, wherein any aryl of R_(e) is optionally substituted with one ormore R_(f); each R_(d) and R_(e) is independently selected from H,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, phenyl, benzyl, and R_(g); each R_(f) isindependently selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, —C(═O)-phenyl, and—C(═O)CH₂C(═O)-phenyl, wherein any phenyl is optionally substituted withone or more groups independently selected from (C₁-C₆)alkyl, —SO₃H, and(C₁-C₆)alkoxy; each R_(g) is

each Z¹ is independently selected from (C₁-C₆)alkyl, halogen, —CN,—OR_(n1), —NR_(q1)R_(r1), —NR_(n1)COR_(p1), —NR_(n1)CO₂R_(p1), NO₂,—C(O)R_(n1), —C(O)OR_(n1) and —C(O)NR_(q1)R_(r1), wherein any(C₁-C₆)alkyl of Z¹ is optionally substituted with one or more (e.g. 1,2, 3, 4, 5 or 6) halogen; each R_(n1) is independently selected from Hand (C₁-C₆)alkyl, wherein any (C₁-C₆)alkyl of R_(n1) is optionallysubstituted with one or more (e.g. 1, 2, 3, 4, 5 or 6) halogen; eachR_(p1) is independently (C₁-C₆)alkyl and R_(q1) and R_(r1) are eachindependently selected from H and (C₁-C₆)alkyl or R_(q) and R_(r1)together with the nitrogen to which they are attached form a piperidine,pyrrolidine, morpholine, azetidine, thiomorpholine, piperazine or4-methylpiperazine; or a salt thereof.
 6. The method of claim 5 whereinthe wherein the sunless tanning composition comprises a compound offormula I selected from:

or a salt thereof.
 7. A method of stimulating pigmentation in mammalianskin, comprising administering to mammalian skin in need thereof, aneffective amount of a sunless tanning composition comprising a compoundof formula I:

wherein: each R¹ is independently H, (C₁-C₆)alkyl, (C₃-C₇)carbocycle orR_(a)C(═O)—, and the two R⁴ groups together form a —(C₃-C₈)alkyl- group,a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl- group or a—(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; or each R⁴ is independently H,(C₁-C₆)alkyl, (C₃-C₇)carbocycle or R_(a)C(═O)—, and the two R¹ groupstogether form a —(C₃-C₈)alkyl- group, a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl-group or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; or the two R⁴ groupstogether form a —(C₃-C₈)alkyl- group, a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkylgroup or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group and the two R¹ groupstogether form a —(C₃-C₈)alkyl- group, a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl-group or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; the dashed bondslabeled “a” are absent and the dashed bonds labeled “b” are doublebonds; or all the dashed bonds are single bonds; R² is H, (C₁-C₆)alkylor aryl, wherein aryl is optionally substituted with one or more Z¹groups; R³ is H, (C₁-C₆)alkyl or aryl, wherein aryl is optionallysubstituted with one or more Z¹ groups; Y is O, S, NH, NR_(c), P, P(═O)or POH; Y′ is Si(R_(b))₂ or —Si(R_(b))₂—O—Si(R_(b))₂—; each R_(a) isindependently (C₁-C₆)alkyl, (C₃-C₇)carbocycle or aryl, wherein aryl isoptionally substituted with one or more Z¹ groups; each R_(b) isindependently (C₁-C₆)alkyl, (C₃-C₇)carbocycle or aryl, wherein aryl isoptionally substituted with one or more Z¹ groups; each R_(c) isindependently R_(g) or a C₁-C₁₈ saturated or unsaturated carbon chainthat is optionally substituted with one or more groups independentlyselected from oxo (═O), hydroxy, mercapto, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, NR_(d)R_(e), carboxy, andaryl, wherein any aryl of R_(c) is optionally substituted with one ormore R_(f); each R_(d) and R_(c) is independently selected from H,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, phenyl, benzyl, and R_(g); each R_(f) isindependently selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, —C(═O)-phenyl, and—C(═O)CH₂C(═O)-phenyl, wherein any phenyl is optionally substituted withone or more groups independently selected from (C₁-C₆)alkyl, —SO₃H, and(C₁-C₆)alkoxy; each R_(g) is

each Z¹ is independently selected from (C₁-C₆)alkyl, halogen, —CN,—OR_(n1), —NR_(q1)R_(r1), —NR_(n1)COR_(p1), —NR_(n1)CO₂R_(p1), NO₂,—C(O)R_(n1), —C(O)OR_(n1) and —C(O)NR_(q1)R_(r1), wherein any(C₁-C₆)alkyl of Z¹ is optionally substituted with one or more (e.g. 1,2, 3, 4, 5 or 6) halogen; each R_(n1) is independently selected from Hand (C₁-C₆)alkyl, wherein any (C₁-C₆)alkyl of R_(n1) is optionallysubstituted with one or more (e.g. 1, 2, 3, 4, 5 or 6) halogen; each R₁is independently (C₁-C₆)alkyl; and R_(q1) and R_(r1) are eachindependently selected from H and (C₁-C₆)alkyl or R_(q1) and R_(r1)together with the nitrogen to which they are attached form a piperidine,pyrrolidine, morpholine, azetidine, thiomorpholine, piperazine or4-methylpiperazine; or a salt thereof.
 8. The method of claim 7 whereinthe wherein the sunless tanning composition comprises a compound offormula I selected from:

or a salt thereof.
 9. A method of stimulating the production of melaninin melanocytes in skin of a mammal, comprising administering tomammalian skin in need thereof, an effective amount of a sunless tanningcomposition comprising a compound of formula I:

wherein: each R¹ is independently H, (C₁-C₆)alkyl, (C₃-C₇)carbocycle orR_(a)C(═O)—, and the two R⁴ groups together form a —(C₃-C₅)alkyl- group,a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl- group or a—(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; or each R⁴ is independently H,(C₁-C₆)alkyl, (C₃-C₇)carbocycle or R_(a)C(═O)—, and the two R¹ groupstogether form a —(C₃-C₅)alkyl- group, a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl-group or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; or the two R⁴ groupstogether form a —(C₃-C₅)alkyl- group, a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkylgroup or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group and the two R¹ groupstogether form a —(C₃-C₈)alkyl- group, a —(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl-group or a —(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl- group; the dashed bondslabeled “a” are absent and the dashed bonds labeled “b” are doublebonds; or all the dashed bonds are single bonds; R² is H, (C₁-C₆)alkylor aryl, wherein aryl is optionally substituted with one or more Z¹groups; R³ is H, (C₁-C₆)alkyl or aryl, wherein aryl is optionallysubstituted with one or more Z¹ groups; Y is O, S, NH, NR_(c), P, P(═O)or POH; Y′ is Si(R_(b))₂ or —Si(R_(b))₂—O—Si(R_(b))₂—; each R_(a) isindependently (C₁-C₆)alkyl, (C₃-C₇)carbocycle or aryl, wherein aryl isoptionally substituted with one or more Z¹ groups; each R_(b) isindependently (C₁-C₆)alkyl, (C₃-C₇)carbocycle or aryl, wherein aryl isoptionally substituted with one or more Z¹ groups; each R_(c) isindependently R_(g) or a C₁-C₁₈ saturated or unsaturated carbon chainthat is optionally substituted with one or more groups independentlyselected from oxo (═O), hydroxy, mercapto, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, NR_(d)R_(e), carboxy, andaryl, wherein any aryl of R_(e) is optionally substituted with one ormore R_(f); each R_(d) and R_(e) is independently selected from H,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, phenyl, benzyl, and R_(g); each R_(f) isindependently selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, —C(═O)-phenyl, and—C(═O)CH₂C(═O)-phenyl, wherein any phenyl is optionally substituted withone or more groups independently selected from (C₁-C₆)alkyl, —SO₃H, and(C₁-C₆)alkoxy: each R_(g) is

each Z¹ is independently selected from (C₁-C₆)alkyl, halogen, —CN,—OR_(n1), —NR_(q1)R_(r1), —NR_(n1)COR_(p1), —NR_(n1)CO₂R_(p1), NO₂,—C(O)R_(n1), —C(O)OR_(n1) and —C(O)NR_(q1)R_(r1), wherein any(C₁-C₆)alkyl of Z¹ is optionally substituted with one or more (e.g. 1,2, 3, 4, 5 or 6) halogen; each R_(n1) is independently selected from Hand (C₁-C₆)alkyl, wherein any (C₁-C₆)alkyl of R_(n1) is optionallysubstituted with one or more (e.g. 1, 2, 3, 4, 5 or 6) halogen; eachR_(p1) is independently (C₁-C₆)alkyl; and R_(q1) and R_(r1) are eachindependently selected from H and (C₁-C₆)alkyl or R_(q1) and R_(r1)together with the nitrogen to which they are attached form a piperidine,pyrrolidine, morpholine, azetidine, thiomorpholine, piperazine or4-methylpiperazine; or a salt thereof.
 10. The method of claim 9 whereinthe wherein the sunless tanning composition comprises a compound offormula I selected from:

or a salt thereof.